Dissertation zur Erlangung des Doktorgrades
der Fakultät für Chemie und Pharmazie
der Ludwig-Maximilians-Universität München
Full Functionalization of the Thieno[3,2-b]thiophene Scaffold.
Benzo[b]thiophenes via Intramolecular Carbomagnesiation of
Alkynyl(aryl)thioethers.
Preparation and Reactions of Solid Organozinc Reagents
von
Thomas Kunz
aus
München
2011
Erklärung
Diese Dissertation wurde im Sinne von § 13 Abs. 3 bzw. 4 der Promotionsordnung vom 29.
Januar 1998 (in der Fassung der sechsten Änderungssatzung vom 16. August 2010) von
Professor Dr. Paul Knochel betreut.
Ehrenwörtliche Versicherung
Diese Dissertation wurde selbständig und ohne unerlaubte Hilfe bearbeitet.
München, 28. September 2011
___________________
Thomas Kunz
Dissertation eingereicht am: 30. September 2011
1. Gutachter: Prof. Dr. Paul Knochel
2. Gutachter: Prof. Dr. Manfred Heuschmann
Mündliche Prüfung am: 7. November 2011
This work was carried out from September 2009 to August 2011 under the guidance of Prof. Dr.
Paul Knochel at the Department of Chemistry of the Ludwig-Maximilians-Universität Munich.
First of all, I thank Prof. Dr. Paul Knochel for accepting me as a PhD student in his group,
for his support and advice in the course of my research and for his interest in this work.
I would like to express my appreciation to Prof. Dr. Manfred Heuschmann for agreeing to
be second reviewer of this thesis and I thank all members of my defense committee – Prof. Dr.
Konstantin Karaghiosoff, Prof. Dr. Heinz Langhals, Prof. Dr. Thomas Bein and Prof. Dr.
Thomas Klapötke for their interest shown in this manuscript by accepting to be referees.
My thanks go to my dear friend and wingman Sebastian Bernhardt for the great scientific
cooperation and, distinctly, for everything we achieved outside of the laboratory. I also express
my gratitude to my soulmate Tobias Blümke for too much to be listed here. Thanks for coping
with me for so long.
I am grateful to Andreas Wagner for the thorough proofreading of this manuscript. I thank
the former members of the materials research team of this workgroup, Dr. Marcel Kienle and Dr.
Silvia Zimdars, for all the fruitful and constructive get-togethers. Thanks, also, to Veronika
Werner, Mirjam Dogru, Dr. Dana Medina and Dr. Andreas Sonnauer for our strong
collaboration.
Also I express my thanks to all past and present members of this workgroup who are
striving hard to make the work environment pleasant and productive in many ways.
I would like to thank the permanent staff of the group, Renate Schröder, Julia Tsvik,
Vladimir Malakhov and Simon Matthe for their help and support with the every-day business and
everything that comes along unexpectedly.
I express my profound gratitude to my parents, my brother, Lottchen, and the close family
for their continuous moral support and patience, their advice, and their trust in me.
Parts of this PhD Thesis have been published:
Thomas Kunz, Paul Knochel: “Selective Multiple Magnesiations of the Thieno[3,2-
b]thiophene Scaffold”, Chemistry - A European Journal 2011, 17(3), 866-872.
Sebastian Bernhardt, Georg Manolikakes, Thomas Kunz, Paul Knochel: “Preparation of Solid
Salt-Stabilized Functionalized Organozincs – Application to Cross-Couplings and
Carbonyl Additions”, Angew. Chem. Int. Ed. 2011, 50, 9205-9208; Angew. Chem. 2011, 123, 9372-
9375.
Thomas Kunz, Paul Knochel: “Preparation of Functionalized Benzo[b]thiophenes via an
Intramolecular Copper-Catalyzed Carbomagnesiation of Alkynyl(aryl)thioethers”,
submitted for publication.
To my family
It is better to remain silent and be thought a fool
than to open one's mouth and remove all doubt.
- Abraham Lincoln -
A. INTRODUCTION .............................................................................................................................1
1. OVERVIEW....................................................................................................................... 2
2. FUNCTIONALIZATION OF THIENO[3,2-b]THIOPHENE........................................... 4
3. FUNCTIONALIZED BENZO[b]THIOPHENES.............................................................. 7
4. SOLID ORGANOZINC REAGENTS............................................................................. 10
B. RESULTS AND DISCUSSION ....................................................................................................12
1. FUNCTIONALIZATION OF THIENO[3,2-b]THIOPHENE......................................... 13
1.1 Precursor Synthesis .................................................................................................... 13
1.2 Preparation of 3,6-Disubstituted 2,5-Dichlorothieno[3,2-b]thiophenes..................... 15
1.3 Preparation of 3,6-Disubstituted Thieno[3,2-b]thiophenes........................................ 17
1.4 Preparation of Fully Functionalized Thieno[3,2-b]thiophenes .................................. 18
1.5 Direct Magnesium Insertion into Substituted 2,5-Dichlorothieno[3,2-b]thiophenes. 20
1.6 Preparation of Fused Pyridazines ............................................................................... 21
1.7 Preparation of Thieno[3,2-b]thiophene Oligomers .................................................... 23
2. BENZO[b]THIOPHENES VIA INTRAMOLECULAR CYCLIZATION ..................... 25
2.1 Precursor Synthesis .................................................................................................... 25
2.2 Cyclization of TMS-substituted Alkynyl(aryl)thioethers .......................................... 27
2.3 Transformation of the Silyl Protection Group............................................................ 31
2.4 Further Functionalization of the Benzo[b]thiophene Scaffold................................... 33
2.5 Cyclization of TIPS-protected Alkynyl(aryl)thioethers ............................................. 35
2.5 Diversification of Polyfunctional Benzothiophenes to new Heterocyclic Scaffolds . 38
3. PREPARATION AND REACTIONS OF SOLID ORGANOZINC REAGENTS......... 39
3.1 Preparation of Solid Salt-Stabilized Functionalized Organozinc Reagents ............... 39
3.2 Application in Negishi Cross-Coupling Reactions .................................................... 40
3.3 Reactivity-Tuning of Organozinc Reagents ............................................................... 43
4. SUMMARY ..................................................................................................................... 44
4.1 Functionalization of Thieno[3,2-b]thiophene ............................................................ 44
4.2 Benzo[b]thiophenes via Intramolecular Carbomagnesiation ..................................... 46
4.3 Preparation and Reactions of Solid Functionalized Organozinc Reagents ................ 48
C. EXPERIMENTAL SECTION......................................................................................................49
1. GENERAL CONSIDERATIONS.................................................................................... 50
1.1 Solvents ...................................................................................................................... 50
1.2 Reagents ..................................................................................................................... 51
1.3 Content Determination of Organometallic Reagents ................................................. 51
1.4 Analytical data............................................................................................................ 52
2. TYPICAL PROCEDURES.............................................................................................. 53
3. PRODUCT SYNTHESIS AND ANALYTICAL DATA ................................................ 58
3.1 Functionalization of Thieno[3,2-b]thiophene ............................................................ 58
Preparation of 3,6-Disubstituted 2,5-Dichlorothieno[3,2-b]thiophenes....................... 58
Preparation of 3,6-Disubstituted Thieno[3,2-b]thiophenes.......................................... 68
Preparation of Fully Functionalized Thieno[3,2-b]thiophenes .................................... 72
Direct Magnesium Insertion into Substituted 2,5-Dichlorothieno[3,2-b]thiophenes... 81
Preparation of Fused Pyridazines................................................................................. 83
Preparation of Thieno[3,2-b]thiophene Oligomers ...................................................... 88
3.2 Benzo[b]thiophenes via Intramolecular Carbomagnesiation ..................................... 95
Preparation of ortho-Dihaloarenes ............................................................................... 95
Preparation of Organic Disulfides................................................................................ 98
Preparation of Sulfonothioate Electrophiles .............................................................. 101
Preparation of Alkynyl(aryl)thioethers ...................................................................... 105
Cyclization of TMS-protected Alkynyl(aryl)thioethers ............................................. 111
Transformation of the Silyl Protection Group............................................................ 125
3.3 Preparation and Reactions of Solid Functionalized Organozinc Reagents .............. 153
Preparation of Organozinc-Reagents ......................................................................... 153
Preparation of Cross-Coupling Products.................................................................... 158
Preparation of Carbonyl Addition Products ............................................................... 165
D. APPENDIX.......................................................................................................................................166
List of Abbreviations
Ac acetyl
aq. aqueous
Ar aryl
ATR attenuated total reflection (IR)
Boc2O di-tert-butyl dicarbonate
br broad (NMR)
Bu butyl
conc. concentrated
d doublet (NMR)
dba trans,trans-dibenzylideneacetone
dist. distilled
DCE 1,2-dichloroethane
DCM dichloromethane
DMAP 4-(dimethylamino)pyridine
DMF N,N-dimethylformamide
DMP Dess-Martin periodinane
equiv equivalent
E electrophile
EI electron ionization
ESI electrospray ionization
Et ethyl
FG functional group
GC gas chromatography
h hour
HRMS high resolution mass spectroscopy
iPr iso-propyl
IR infrared
J coupling constant (NMR)
M mol/L
m meta
Me methyl
min minute
Mp. melting point
MS mass spectroscopy
MW microwave
NBS N-bromosuccinimide
NCS N-chlorosuccinimide
NMR nuclear magnetic resonance
NMP N-methylpyrrolidin-2-one
o ortho
OPiv pivalate
p para
PEPPSI-iPr [1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)
dichloride
Ph phenyl
ppm parts per million
R organic substituent
sat. saturated
S-Phos 2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl
t-Bu tert-butyl
t reaction time
TBAF Tetra-n-butylammonium fluoride
tfp tris(2-furyl)phosphine
TEA triethyl amine
THF tetrahydrofuran
TIPS triisopropylsilyl
TLC thin layer chromatography
TMP 2,2,6,6-tetramethylpiperidyl
TMS trimethylsilyl
TP typical procedure
A. INTRODUCTION
A. INTRODUCTION
2
1. OVERVIEW
The foundation of organic chemistry as a veritable scientific discipline is marked by the
syntheses of oxalic acid from cyanogen and urea from ammonium cyanate which have been
undertaken by Wöhler in the years 1824 and 1828. Two centuries have elapsed since then and
considerable improvements have been made in the development of analytical tools and synthetic
techniques. The discovery of nuclear magnetic resonance (NMR) spectroscopy1 represents a
milestone in innovation towards sophisticated analytical instruments of today’s routine.
Considering modern synthetic methods, organometallic chemistry has been established as one of
the most significant disciplines in the field of preparative organic chemistry. Since the first report
of a carbon-metal bond, based on Frankland’s finding of diethyl zinc in the 19th century,2
organometallic species have become increasingly important as valuable intermediates. The
synthetic utility of their polarized carbon-metal bond has been shown time and time again in the
elaboration of complex organic molecules. Another landmark in the rise of organometallic
chemistry was set by Grignard’s accomplishments on organomagnesium reagents at the
beginning of the 20th century.3
Aside from zinc and magnesium, a wide range of metals has been investigated since then
and numerous applications of organometallics as catalysts and reagents have emerged in organic
synthesis.4 The chemical reactivity of the respective organometallic species is based on the
difference of electronegativity of the binding partners, resulting in a more or less polarized
carbon-metal bond. Their performance is moreover influenced by the inherent properties of the
element as main-group or transition-metal. A strongly polarized carbon-metal bond is found in
organolithium and organomagnesium compounds and displays high reactivity along with low
selectivity of the reaction site in organic transformations.5 An increasingly covalent character of
the carbon-metal bond, which is represented by boron, zinc or tin species, improves stability and
versatility of the reagent, but is paired with decreasing reactivity towards other reactants.6
1 P. J. Hore, Nuclear Magnetic Resonance, Oxford University Press, Oxford, 1995.
2 a) E. Frankland, Liebigs Ann. Chem. 1848, 71, 171; b) E. Frankland, J. Chem. Soc. 1848, 2, 263.
3 a) V. Grignard, Ann. Chim. 1901, 24, 433; b) V. Grignard, Compt. Rend. Acad. Sci. Paris 1900, 130, 1322.
4 a) P. Knochel, (Ed.) Handbook of Functionalized Organometallics, Vol. 1 and 2, Wiley-VCH, Weinheim, Germany, 2005;
b) Transition Metals for Organic Synthesis (Eds.: M. Beller, C. Bolm), Wiley-VCH, Weinheim, Germany, 2004.
5 G. Wu, M. Huang, Chem. Rev. 2006, 106, 2596.
6 N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457.
A. INTRODUCTION
3
The first and foremost application of organometallic compounds was the construction of
organic frameworks. However today, these methodologies have been adapted to the synthesis of
scaffolds comprising carbon-heteroatom bonds via organometallic procedures. At the same time
environmental and economic issues7 are urging for ongoing development and further
improvements in this field. The relevance of sustainable chemistry becomes obvious with limited
resources and increasing environmental pollution opposing the vast demand for novel
agrochemicals and pharmaceutical substances.8 In the modern society, essential innovations of
the chemical sector are widespread, but often subtle. This is evident considering the numerous
industrial branches that depend on advancements in chemical industry to maintain economic
growth and prosperity of our modern civilization.9 To meet these permanently changing
requirements, ongoing research activities and technological progress in chemistry become
inevitable endeavors and are a major motivation for present day scientists.
7 a) B. M. Trost, Angew. Chem. Int. Ed. 1995, 34, 259; b) C.-J. Li, B. M. Trost, Proc. Nat. Acad. Sci. 2008, 105, 13197.
8 a) T. Collins, Science 2001, 291, 48; b) C. Okkerse, H. van Bekkum, Green Chemistry 1999, 1, 107.
9 S. Kuznets, Amer. Econ. Rev. 1973, 63, 247.
A. INTRODUCTION FUNCTIONALIZATION OF THIENO[3,2-b]THIOPHENE
4
2. FUNCTIONALIZATION OF THIENO[3,2-b]THIOPHENE
In the research field of material chemistry, molecular electronics and electronic devices
have rapidly gained interest. Besides organic light-emitting diodes (OLEDs)10 and organic field-
effect transistors (FETs),11 organic photovoltaics12 have attracted intensive attention in the
research for a reliable alternative energy supply. The different approaches to construct organic
solar cells are based on bulk heterojunction, small molecule or nanorod systems,13 consisting of
various donor-acceptor interactions.14 Improvement of these donor-acceptor systems depends on
advances in morphology of the materials as well as their molecular structure.15 Among the donor
polymers, functional oligothiophenes or fused S-heterocycles are predominant.16 More recently
thienothiophenes, in particular the thieno[3,2-b]thiophene scaffold, have attracted intensive
investigation as these moieties comprise some significant advantages including centrosymmetry
and higher rigidity over the universally employed thiophene building-block.17
10 a) X. Gong, M. R. Robinson, J. C. Ostrowski, D. Moses, G. C. Bazan, A. J. Heeger, Adv. Mater. 2002, 14, 581; b)
M. D. Curtis, J. Cao, J. W. Kampf, J. Am. Chem. Soc. 2004, 126, 4318; c) P. L. Burn, S. C. Lo, I. D. W. Samuel, Adv.
Mater. 2007, 19, 1675; d) Organic Light-Emitting Devices (Eds.: K. Müllen, U. Scherf), Wiley VCH, Weinheim, 2006.
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2009, 21, 213; b) P. Brocorens, A. Van Vooren, M. L. Chabinyc, M. F. Toney, M. Shkunov, M. Heeney, I.
McCulloch, J. Cornil, R. Lazzaroni, Adv. Mater. 2009, 21, 1193; c) M. Halik, H. Klauk, U. Zschieschang, G. Schimd,
S. Ponomarenko, S. Kirchmeyer, W. Weber, Adv. Mater. 2003, 15, 917; d) A. R. Murphy, J. M. J. Fréchet, Chem. Rev.
2007, 107, 1066.
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1949; Angew. Chem. Int. Ed. 2008, 47, 1923.
13 a) C. J. Brabec, N. S. Sariciftci, J. C. Hummelen, Adv. Funct. Mater. 2001, 11, 15; b) C. W. Tang, Appl. Phys. Lett.
1986, 48, 183; c) W. U. Huynh, J. J. Dittmer, A. P. Alivisatos, Science 2002, 295, 2425.
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Chem. 2003, 115, 3493; Angew. Chem. Int. Ed. 2003, 42, 3371; b) M. Granström, K. Petritsch, A. C. Arias, A. Lux, M.
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Rittberger, N. S. Sariciftci, Adv. Funct. Mater. 2003, 13, 85; c) J. Nelson, Curr. Opin. Solid State Mater. Sci. 2002, 6, 87.
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C.-O. Ma, P. Bäuerle, Chem. Rev. 2009, 109, 1141.
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Gundlach, B. Hamadani, R. Hamilton, L. Richter, A. Salleo, M. Shkunov, D. Sparrowe, S. Tierney, W. Zhang, Adv.
Mater. 2009, 21, 1091; b) L. De Cremer, T. Verbiest, G. Koeckelberghs, Macromolecules 2008, 41, 568; c) I. McCulloch,
A. INTRODUCTION FUNCTIONALIZATION OF THIENO[3,2-b]THIOPHENE
5
Direct lithiations are known for all positions of the fused thienothiophene ring, although
selective lithiations on the 3- and 6-positions are only possible via halogen-lithium exchange and
therefore require low temperatures. Furthermore, organolithiums are not compatible with several
important functional groups, like aldehydes, ketones, or esters.18 Direct magnesiation of this
scaffold as an alternative strategy has to the best of our knowledge not been explored.19 Multiple
magnesiations of aromatic and heteroaromatic substrates using the recently developed Mg/Li-
amide base TMPMgCl· LiCl have shown broad applicability and exceptional functional group
tolerance.20
M. Heeney, C. Bailey, K. Genevicius, I. MacDonald, M. Shkunov, D. Sparrowe, S. Tierney, R. Wagner, W. Zhang, M.
L. Chabinyc, R. J. Kline, M. D. McGehee, M. F. Toney, Nat. Mater. 2006, 5, 328; d) N. Hergué, P. Frère, Org. Biomol.
Chem. 2007, 5, 3442; e) X. Zhang, M. Köhler, A. J. Matzger, Macromolecules 2004, 37, 6306; f) M. Melucci, L.
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Perkin Trans. 1 1999, 1273; c) P. Leriche, J.-M. Raimundo, M. Turbiez, V. Monroche, M. Allain, F.-X. Sauvage, J.
Roncali, P. Frère, P. J. Skabara, J. Mater. Chem. 2003, 13, 1324; d) P. Li, B. Ahrens, N. Feeder, P. R. Raithby, S. J.
Teat, M. S. Khan, Dalton Trans. 2005, 874; e) L.S. Fuller, B. Iddon, K.A. Smith, J. Chem. Soc. Perkin Trans. 1 1997,
3465.
19 a) R. E. Mulvey, F. Mongin, M, Uchiyama, Y. Kondo, Angew. Chem. 2007, 119, 3876; Angew. Chem. Int. Ed. 2007,
46, 3802; b) F. Mongin, G. Quéguiner, Tetrahedron 2001, 46, 4059; c) A. Turck, N. Plé, F. Mongin, G. Quéguiner,
Tetrahedron 2001, 57, 4489.
20 a) A. Krasovskiy, V. Krasovskaya, P. Knochel, Angew. Chem. 2006, 118, 3024; Angew. Chem. Int. Ed. 2006, 45, 2958;
b) W. Lin, O. Baron, P. Knochel, Org. Lett. 2006, 8, 5673; c) M. Mosrin, P. Knochel, Org. Lett. 2008, 10, 2497; d) G.
Clososki, C. J. Rohbogner, P. Knochel, Angew. Chem. 2007, 119, 7825; Angew. Chem. Int. Ed. 2007, 46, 7681; e) C. J.
Rohbogner, G. Clososki, P. Knochel, Angew. Chem. 2008, 120, 1526; Angew. Chem. Int. Ed. 2008, 47, 1503; f) F. M.
Piller, P. Knochel, Org. Lett. 2009, 11, 445.
A. INTRODUCTION FUNCTIONALIZATION OF THIENO[3,2-b]THIOPHENE
6
The objective of this topic was the full functionalization of the thieno[3,2-b]thiophene ring
starting from readily available 2,5-dichlorothieno[3,2-b]thiophene21 (2) using the TMPMgCl· LiCl
base (1). The goal was the incorporation of sensitive functional groups which could be tolerated
in further modifications leading to highly diverse compounds that were so far inaccessible.
In a general reaction strategy, the dichlorothienothiophene 2 was metalated sequentially at
the 3- and 6-position with base 1 and led, after quenching with various electrophiles, to
substituted thienothiophenes of type 5. After the reductive cleavage of the C-Cl bonds, the
intermediates of type 6 were then regioselectively deprotonated at the 2- and 5-positions, again
using TMPMgCl· LiCl (1), leading to fully functionalized thieno[3,2-b]thiophenes of type 8
(Scheme 1).
Scheme 1: Reaction sequence allowing the conversion of 2,5-dichlorothieno-[3,2-
b]thiophene 2 to fully functionalized thienothiophenes of type 8.
21 Prepared by a modified literature procedure; cf. experimental section. P. Li, B. Ahrens, N. Feeder, P. R. Raithby, S.
J. Teat, M. S. Khan, Dalton Trans. 2005, 874.
A. INTRODUCTION FUNCTIONALIZED BENZO[b]THIOPHENES
7
3. FUNCTIONALIZED BENZO[b]THIOPHENES
The synthesis of functionalized heterocycles and novel heterocyclic scaffolds is an
important topic in synthetic organic chemistry since these ring systems have potential
applications as pharmaceuticals or in material science.22 Several methodologies for the
construction of indoles, benzofuranes, benzothiophenes and other fused compounds via
cyclization reactions have been reported.23 The preparation by ring-closing procedures includes
metalative cyclizations,23b,24 gold-catalyzed reactions, 23a,25 copper-promoted halocyclizations, 26 and
palladium-mediated iodocyclizations. 23d,27,28
Among these heterocyclic scaffolds the benzo[b]thiophene motive29 is of particular interest,
as it is often found in biologically active molecules such as raloxifene30 or potential drug
candidates31 and is moreover widespread in material chemistry.17a,32 Recently, Larock applied a
22 J. Alvarez-Builla, J. J. Vaquero, J. Barluenga in Modern Heterocyclic Chemistry (Eds.: J. Alvarez-Builla, J. J. Vaquero, J.
Barluenga), Wiley-VCH, Weinheim, 2011.
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25 I. Nakamura, T. Sato, Y. Yamamoto, Angew. Chem. Int. Ed. 2006, 45, 4473.
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Med. Chem. Lett. 1999, 9, 1081; c) C. D. Jones, M. G. Jevnikar, A. J. Pike, M. K. Peters, L. J. Black, A. R.
Thompson, J. F. Falcone, J. A. Clemes, J. Med. Chem. 1984, 27, 1057.
A. INTRODUCTION FUNCTIONALIZED BENZO[b]THIOPHENES
8
palladium-catalyzed iodocyclization reaction sequence for the elaboration of systems bearing
multiple benzo[b]thiophene units.33 A novel tandem reaction consisting of an intramolecular S-
vinylation and a subsequent intermolecular C-C bond formation has lately been reported by
Lautens.34 This new carbon-sulfur coupling reaction provides functionalized benzo[b]thiophenes
in a single step. However, since sulfur tends to poison catalyst systems, 35 and ortho-alkynyl
benzenethiols are not accessible by Sonogashira coupling36 we envisioned a metalative cyclization
procedure that uses readily available alkynyl thioethers and thus avoids employing free thiols.
This work was aimed at a mild and general method for the preparation of functionalized
benzo[b]thiophenes and benzo[b]thieno[2,3-d]thiophenes via an intramolecular catalytic
carbocupration37 of alkynyl(aryl)thioethers. This cyclization reaction was catalyzed by the THF-
soluble copper(I)-salt CuCN· 2 LiCl, and the tolerance towards functional groups in the
molecular scaffold was investigated. By using activated alkynyl moieties in the substrates,
cyclization without copper catalyst was attempted, improving this protocol to a straightforward
and atom-economical38 process in heterocycle synthesis. The scope of the methodology was
explored by further modifications of the cyclization products affording highly diversified
benzothiophenes and novel heterocyclic compounds derived thereof.
32 T. Y. Zhang, J. O’Toole, C. S. Proctor, Sulfur Rep. 1999, 22, 1.
33 S. Mehta, R. C. Larock, J. Org. Chem. 2010, 75, 1652.
34 C. S. Bryan, J. A. Braunger, M. Lautens, Angew. Chem. Int. Ed. 2009, 48, 7064.
35 a) E. Alvaro, J. F. Hartwig, J. Am. Chem. Soc. 2009, 131, 7858; b) G. Mann, D. Barañano, J. F. Hartwig, A. L.
Rheingold, I. A. Guzei, J. Am. Chem. Soc. 1998, 120, 9205.
36 A. M. Malte, C. E. Castro, J. Am. Chem. Soc. 1967, 89, 6770.
37 a) J. P. Das, H. Chechik, I. Marek, Nat. Chem. 2009, 1, 128; b) A. Abramovitch, I. Marek, Eur. J. Org. Chem. 2008,
4924; c) I. Marek, Chem. Eur. J. 2008, 14, 7460. For reviews on carbocupration reactions see also: d) J. F. Normant,
A. Alexakis, Synthesis 1981, 841; e) A. Basheer, I. Marek, Beilstein J. Org. Chem. 2010, 6, DOI:10.3762/bjoc.6.77.
38 B. M. Trost, Science 1991, 254, 1471.
A. INTRODUCTION FUNCTIONALIZED BENZO[b]THIOPHENES
9
The intended synthetic sequence started from (2-bromophenyl)(alkynyl)thioethers of type
9. These compounds were metalated via a Br/Mg-exchange using i-PrMgCl· LiCl,39 the
intermediate 10 then cyclized to the benzo[b]thiophene 11. This new organometallic reagent could
react with a variety of electrophiles giving access to 2-functionalized benzo[b]thiophenes of type
12 (Scheme 2).
Scheme 2: Preparation of functionalized benzo[b]thiophenes of type 12 by a copper-
catalyzed carbomagnesiation of alkynyl(aryl)thioethers.
These benzothiophenes carried a TMS-substituent, which allowed a further modification
and thus a diversification of the scaffold. The TMS-group could either be transformed into the
desilylated compounds of type 13 or into the 3-iodobenzothiophenes of type 14. The resulting
heterocyclic molecules were valuable intermediates for deprotonation, exchange, or cross-
coupling reactions affording the highly functionalized benzo[b]thiophenes of type 15 and 16
(Scheme 3).
Scheme 3: Intended functionalization of 2-substituted benzo[b]thiophenes of type 12.
39 a) A. Krasovskiy, P. Knochel, Angew. Chem. 2004, 116, 3396; Angew. Chem. Int. Ed. 2004, 43, 3333; b) A.
Krasovskiy, B. F. Straub, P. Knochel, Angew. Chem. 2006, 118, 165; Angew. Chem. Int. Ed. 2006, 45, 159.
A. INTRODUCTION SOLID ORGANOZINC REAGENTS
10
4. SOLID ORGANOZINC REAGENTS
Organozinc reagents have found numerous synthetic applications, especially in the Negishi
cross-coupling reaction.40,41 Various methods for the preparation of organozinc compounds have
been reported.42 However, polyfunctional zinc reagents of type RZnX (X = halide)43 or R2Zn are
highly sensitive towards moisture and air. These properties represent a serious drawback for their
practical use at a laboratory and industrial scale. Thus, the availability of more convenient
organozinc reagents is highly desirable. Since the reactivity of organozinc compounds is strongly
influenced by the presence of salts,44 it was anticipated that the presence of appropriate metallic
salts may lead to an improved stability towards air and moisture. Charette has demonstrated that
alkoxides greatly stabilize zinc carbenoids for enantioselective cyclopropanations,45 while
Herrmann reported that methylzinc acetate can be efficiently used for the synthesis of
methyltrioxorhenium (MTO) even on larger scales.46
40 a) E. Negishi, A. O. King, N. Okukado, J. Org. Chem. 1977, 42, 1821; b) E. Negishi, L. F. Valente, M. Kobayashi, J.
Am. Chem. Soc. 1980, 102, 3298; c) G. Wang, N. Yin, E. Negishi, Chem. Eur. J. 2011, 17, 4118; d) E. Negishi, X.
Zeng, Z. Tan, M. Qian, Q. Hu, Z. Huang in Metal-Catalyzed Cross-Coupling Reactions, 2nd ed. (Eds.: A. de Meijere, F.
Diederich), Wiley-VCH, Weinheim, 2004, pp. 815-877.
41 a) J. E. Milne, S. L. Buchwald, J. Am. Chem. Soc. 2004, 126, 13028; b) C. Han, S. L. Buchwald, J. Am. Chem. Soc.
2009, 131, 7532; c) S. Çalimsiz, M. Sayah, D. Mallik, M. G. Organ, Angew. Chem. 2010, 122, 2058; Angew. Chem. Int.
Ed. 2010, 49, 2014; d) N. Hadei, G. T. Achonduh, C. Valente, C. J. O’Brien, M. G. Organ, Angew. Chem. 2011, 123,
3982; Angew. Chem. Int. Ed. 2011, 50, 3896.
42 a) P. Knochel, H. Leuser, L.-Z. Gong, S. Perrone, F. F. Kneisel in Handbook of Functionalized Organometallics, (Ed.: P.
Knochel), Wiley-VCH, Weinheim, 2005, pp. 251-333; b) P. Knochel, N. Millot, A. L. Rodriguez, C. E. Tucker,
Org. React. 2001, 58, 417; c) A. Lemire, A. Côté, M. K. Janes, A. B. Charette, Aldrichim. Acta 2009, 42, 71.
43 a) P. Knochel, J. J. Almena Perea, P. Jones, Tetrahedron 1998, 54, 8275; b) A. Krasovskiy, V. Malakhov, A.
Gavryushin, P. Knochel, Angew. Chem. 2006, 118, 6186; Angew. Chem. Int. Ed. 2006, 45, 6040; c) N. Boudet, S. Sase,
P. Sinha, C.-Y. Liu, A. Krasovskiy, P. Knochel, J. Am. Chem. Soc. 2007, 129, 12358.
44 a) M. Hatano, K. Ishihara in Acid Catalysis in Modern Organic Synthesis, Vol. 1, (Eds.: H. Yamamoto, K. Ishihara),
Wiley-VCH, Weinheim, 2008, pp. 175-182; b) M. Hatano, S. Suzuki, K. Ishihara, J. Am. Chem. Soc. 2006, 128, 9998;
c) M. Hatano, O. Ito, S. Suzuki, K. Ishihara, Chem. Commun. 2010, 2674; d) L. Jin, C. Liu, J. Liu, F. Hu, Y. Lan, A.
S. Batsanov, J. A. K. Howard, T. D. Marder, A. Lei, J. Am. Chem. Soc. 2009, 131, 16656; e) H. Duan, L. Meng, D.
Bao, H. Zhang, Y. Li, A. Lei, Angew. Chem. 2010, 122, 6531; Angew. Chem. Int. Ed. 2010, 49, 6387; f) K. Murakami,
H. Yorimitsu, K. Oshima, J. Org. Chem. 2009, 74, 1415; g) A. Metzger, S. Bernhardt, G. Manolikakes, P. Knochel,
Angew. Chem. 2010, 122, 4769; Angew. Chem. Int. Ed. 2010, 49, 4665.
45 A. B. Charette, C. Molinaro, C. Brochu, J. Am. Chem. Soc. 2001, 123, 12160.
46 W. A. Herrmann, A. M. J. Rost, J. K. M. Mitterpleininger, N. Szesni, S. Sturm, R. W. Fischer, F. E. Kühn, Angew.
Chem. 2007, 119, 7440; Angew. Chem. Int. Ed. 2007, 46, 7301.
A. INTRODUCTION SOLID ORGANOZINC REAGENTS
11
The focus of this topic lay on the preparation of solid salt-stabilized organozinc reagents
derived from aryl, heteroaryl, and benzylic halides. Obtained in solid form, these compounds
were envisioned to be safer and more convenient to handle. Their properties concerning stability
and reactivity in cross-coupling and addition reactions were to be evaluated.
These new zinc reagents were prepared in a one-pot procedure from the respective organic
halide (17). A magnesium insertion in the presence of zinc pivalate (Zn(OPiv)2· 2 LiCl) followed
by the evaporation of the solvent gave the corresponding organozinc pivalates of type 18 as solid
materials (Scheme 4).
Scheme 4: Preparation of solid organozinc reagents of type 18.
These solid aromatic, heteroaromatic and benzylic zinc reagents underwent palladium-
catalyzed Negishi cross-coupling reactions with various aromatic and heteroaromatic bromides
and chlorides leading to highly functionalized biaryl systems (19; Scheme 5).
Scheme 5: Solid zinc pivalates in Negishi cross-coupling reactions.
B. RESULTS AND DISCUSSION
B. RESULTS AND DISCUSSION FUNCTIONALIZED THIENO[3,2-b]THIOPHENES
13
1. FUNCTIONALIZATION OF THIENO[3,2-b]THIOPHENE
1.1 Precursor Synthesis
Thieno[3,2-b]thiophene was prepared by a slightly modified literature procedure47 from
commercial 3-bromothiophene 20 (Scheme 6). After a Br/Li-exchange reaction, a nucleophilic
substitution on the potassium bromoacetate gave the carboxylic acid 21. A subsequent
intramolecular Friedel-Crafts acylation and reduction of the ketone 22 afforded the thieno[3,2-
b]thiophene 23 in 48% overall yield.
Scheme 6: Preparation of thieno[3,2-b]thiophene 23 via intramolecular Friedel-Crafts acylation.
During the course of the studies a new two-step route towards thieno[3,2-b]thiophene has
been reported, allowing easier preparation in large scale.48 This reaction sequence uses
bis(diethoxyethyl)disulfide as electrophile and the intermediate thioether 24 cyclized
spontaneously upon acidic treatment of the acetal giving the target thieno[3,2-b]thiophene 23 in
51% overall yield (Scheme 7).
Scheme 7: Preparation of thieno[3,2-b]thiophene via electrophilic cyclization.
47 P. Leriche, J.-M. Raimundo, M. Turbiez, V. Monroche, M. Allain, F.-X. Sauvage, J. Roncali, P. Frère, P. J. Skabara,
J. Mater. Chem. 2003, 13, 1324.
48 J. T. Henssler, A. J. Matzger, Org. Lett. 2009, 11, 3144.
B. RESULTS AND DISCUSSION FUNCTIONALIZED THIENO[3,2-b]THIOPHENES
14
2,5-Dichlorothieno[3,2-b]thiophene 2 served as precursor in the functionalization of the
scaffold and was readily available via chlorination of the parent compound with NCS (Scheme 8).
The chlorine atoms assisted as protection groups of the inherently more reactive 2- and 5-
positions of the scaffold and at the same time, these substituents activated the adjacent carbon
positions for a metalation with TMPMgCl· LiCl.
Scheme 8: Chlorination of thieno[3,2-b]thiophene.
B. RESULTS AND DISCUSSION FUNCTIONALIZED THIENO[3,2-b]THIOPHENES
15
1.2 Preparation of 3,6-Disubstituted 2,5-Dichlorothieno[3,2-b]thiophenes
The first metalation of the dichlorothienothiophene 2 with TMPMgCl· LiCl (1; 1.1 equiv)
was achieved at 25 °C within 45 min and after trapping with PhSO2SMe gave the thiomethylated
thienothiophene 4a in 96% yield. A subsequent deprotonation using base 1 (25 °C, 45 min)
afforded the ester 5a in 89% yield after reaction with ethyl cyanoformate (Scheme 9).
Scheme 9: Reaction sequence towards 3,6-disubstituted 2,5-dichlorothieno[3,2-b]thiophenes of type 5.
Similarly, treatment of the magnesiated compound with PhSO2SPh provided the thioether 4b in
85% yield. A further deprotonation of 4b (25 °C, 45 min) and quenching with Boc2O gave the
ester 5b in 70% yield (Table 1, entry 1). The reaction of the magnesiated thienothiophene with
TMSCN afforded compound 4c in 85% yield. Metalation of 4c (25 °C, 45 min) followed by a
Cu(I)-catalyzed acylation49 with benzoyl chloride gave the difunctionalized thienothiophene 5c in
95% yield (entry 2). After transmetalation to zinc, a Pd-catalyzed cross-coupling reaction
(3 mol% Pd(dba)2, 6 mol% tfp)40,41,50 of the thienothiophene intermediate with 1-iodo-4-
methoxybenzene or 1-chloro-4-iodobenzene led to thienothiophenes 4d and 4f in 71-91% yield
(entries 3-6). After metalation of 4d (25 °C, 1 h) the magnesiated intermediate reacted directly
with Boc2O giving product 5d in 73% yield (entry 3). Alternatively, a Cu(I)-catalyzed acylation
reaction with pivaloyl chloride led to ketone 5e in 85% yield (entry 4). Similarly, the
deprotonation of 4f (25 °C, 45 min) afforded, after subsequent acylation with pivaloyl choride, 5f
in 75% yield (entry 5). The reaction with ethyl cyanoformate as second electrophile gave 5g in
81% yield (entry 6). The ester 4h was obtained in 92% yield (entry 7) by trapping the magnesiated
dichlorothienothiophene with ethyl cyanoformate. After a successive metalation (-20 °C, 20 min)
and quenching again with ethyl cyanoformate the diester 5h was isolated in 81% yield. Treatment
of the magnesiated dichlorothienothiophene intermediate with PhSO2SBu afforded thioether 4i
49 P. Knochel, M. C. P. Yeh, S. C. Berk, J. Talbert, J. Org. Chem. 1988, 53, 2390.
50 a) E. Negishi, Acc. Chem. Res. 1982, 15, 340; b) X. Zeng, M. Quian, Q. Hu, E. Negishi, Angew. Chem. 2004, 116,
2309; Angew. Chem. Int. Ed. 2004, 43, 2259; c) K. Tamao, K. Sumitani, M. Kumada, J. Am. Chem. Soc. 1972, 94,
4373; d) K. Tamao, J. Organomet. Chem. 2002, 653, 23; e) V. Farina in Comprehensive Organometallic Chemistry II, Vol. 12
(Eds.: E. W. Abel, F. G. Stone, G. Wilkinson), Pergamon, New York, 1995, 161–241.
B. RESULTS AND DISCUSSION FUNCTIONALIZED THIENO[3,2-b]THIOPHENES
16
in 94% yield. A subsequent deprotonation (25 °C, 45 min) and trapping with ethyl cyanoformate
provided the ester 5i in 83% yield (entry 8).
Table 1: Synthesis of 3,6-disubstituted 2,5-dichlorothieno[3,2-b]thiophenes of type 5.
Entry Electrophile
1
3-Substitution
Product
Electrophile
2
3,6-Disubstitution
Product
1 PhSO2SPh
(85%)
4b
Boc2O
(70%)
5b
2 TMSCN
(85%)
4c
PhCOCl
(95%)[c]
5c
3
(71%)[b] 4d
Boc2O
(73%)
5d
4
(71%)[b]
4d t-BuCOCl (85%)[c]
S
S
Cl
Cl
t-BuOC
OMe
5e
5
(91%)[b] 4f
t-BuCOCl (75%)[c]
5f
6
(91%)[b]
4f NCCO2Et
(81%)
5g
7 NCCO2Et
(92%)
4h
NCCO2Et (81%)
5h
8 PhSO2SBu
(94%)
4i
NCCO2Et (83%)
5i
[a] Isolated yield of analytically pure product. [b] After transmetalation using ZnCl2 (1.1 equiv) and a cross-
coupling reaction (Pd(dba)2 3 mol%, tfp 6 mol%). [c] After transmetalation using CuCN· 2 LiCl (20 mol %).
B. RESULTS AND DISCUSSION FUNCTIONALIZED THIENO[3,2-b]THIOPHENES
17
1.3 Preparation of 3,6-Disubstituted Thieno[3,2-b]thiophenes
The best method for the reductive cleavage of the C-Cl bonds was the reduction method
developed by Schlosser using Pd/C and ammonium formate.51 As conventional heating led to a
sluggish reaction, microwave irradiation (120 °C, 100 W) was used. This enhanced the reaction
rate, so that the reduction of the dichlorothieno[3,2-b]thiophene 5a was complete within 6 h
giving 6a in 77% yield (Scheme 10).
Scheme 10: Microwave-enhanced dechlorination of the C2 and C5 position.
This procedure has also been used for the reduction of other dichlorothienothiophenes of
type 5 (120 °C, 100 W, 4-6 h) furnishing the dechlorinated products 6a-g in 71-85% yield
(Scheme 11). Remarkably, this reduction is compatible with other aromatic C-Cl-bonds
(compound 6e).
Scheme 11: 3,6-Disubstituted thieno[3,2-b]thiophenes of type 6.
51 a) E. Mazri, C. Bobbio, F. Cottet, M. Schlosser, Eur. J. Org. Chem. 2005, 2116; b) C. Bobbio, T. Rausis, M.
Schlosser, Chem. Eur. J. 2005, 11, 1903. Other metal-catalyzed reactions can be employed, for a review see: F.
Alonso, I. P. Beletskaya, M. Yus, Chem. Rev. 2002, 102, 4009.
B. RESULTS AND DISCUSSION FUNCTIONALIZED THIENO[3,2-b]THIOPHENES
18
1.4 Preparation of Fully Functionalized Thieno[3,2-b]thiophenes
A further deprotonation of the dechlorinated thienothiophenes of type 6 was achieved with
complete regioselectivity. When treating the thienothiophene 6a with TMPMgCl· LiCl (1;
1.1 equiv, -20 °C, 40 min), the ester moiety is acting as a directing group52 and magnesiation
occurred regioselectively on the adjacent carbon atom. Succeeding Pd-catalyzed cross-coupling
reactions with 4-iodoanisole or 4-iodobenzotrifluoride, a Cu(I)-catalyzed acylation reaction with
pivaloyl chloride or direct quenching with PhSO2SPh gave the expected products 7a-d in 91-94%
yield. Similarly, a ketone proved to be an efficient directing group. After deprotonation of 6g (-
50 °C, 20 min) and trapping with PhSO2SMe the thioether 7e was isolated in 94% yield. The
polyfunctionalized heterocycle 7f was obtained in 77% yield after an acylation with 4-
chlorobenzoyl chloride. Magnesiation of 6d (-20 °C, 30 min) and subsequent reaction with
dibromotetrachloroethane afforded the bromo-substituted thienothiophene 7g in 90% return
(Scheme 12) which again served as a building block in the oligomer synthesis (Scheme 18).
S
S
EtO2C
SMe
S
SMeS
t-BuOC
OMe
S
S
EtO2C
SMe
1) TMPMgCl·LiCl2) ZnCl23) Pd(dba)2, tfp
IMeO
MeO
7a; 91%
S
S
EtO2C
SMe
F3C
7b; 92%S
St-BuOC
EtO2C
SMe
7c; 94%
S
SPhS
EtO2C
SMe
7d; 91%
7e; 94%S
SClp-C6H4OC
t-BuOC
OMe
7f; 77%
S
S
SBu
EtO2C
7g; 90%
Br
6a
Scheme 12: Trifunctionalized thieno[3,2-b]thiophenes of type 7.
52 a) T. Macklin, V. Snieckus, in Handbook of C–H Transformations (Ed.: G. Dyker), Wiley-VCH, Weinheim, 2005, 106;
b) C. G. Hartung, V. Snieckus in Modern Arene Chemistry (Ed.: D. Astruc ), Wiley-VCH, Weinheim, 2002, 330.
B. RESULTS AND DISCUSSION FUNCTIONALIZED THIENO[3,2-b]THIOPHENES
19
The remaining 5-position could again be metalated with TMPMgCl· LiCl (1).
Deprotonation of 7b (-20 °C, 40 min) followed by a Cu(I)-catalyzed acylation using pivaloyl
chloride gave the polyfunctionalized heterocycle 8a in 80% yield. After metalation of 7c (-40 °C,
15 min) and a Pd-catalyzed cross-coupling reaction with 1-fluoro-4-iodobenzene, the fully
functionalized thieno[3,2-b]thiophene 8b was isolated in 81% yield. Similarly, compound 8c was
obtained in 81% yield after deprotonating thienothiophene 7e (0 °C, 90 min) and trapping the
resulting magnesiated species with ethyl cyanoformate. The treatment of the diester 6b with
TMPMgCl· LiCl (1) directly led to a bis-magnesiated intermediate (2.2 equiv, -40 °C, 20 min)
which could be acylated with pivaloyl chloride in 72% yield (8d) or allylated with ethyl 2-
(bromomethyl)acrylate53 affording 8e in 77% yield (Scheme 13).
Scheme 13: Fully functionalized thieno[3,2-b]thiophenes of type 8.
53 J. Villieras, M. Rambaud, Synthesis 1982, 924.
B. RESULTS AND DISCUSSION FUNCTIONALIZED THIENO[3,2-b]THIOPHENES
20
1.5 Direct Magnesium Insertion into Substituted 2,5-Dichlorothieno[3,2-b]thiophenes
Recently, we have reported a LiCl-mediated magnesium insertion into aryl chlorides and
bromides under mild and convenient conditions.54 By using this method, the
dichlorothienothiophenes of type 5 were also directly magnesiated. Thus, the addition of the
dichlorothienothiophene 5a to Mg turnings (2.5 equiv), LiCl (1.25 equiv) and ZnCl2 (1.1 equiv) in
THF regioselectively gave the zincated intermediate 25 (25 °C, 1 h) which could be arylated via a
Pd-catalyzed cross-coupling reaction (3 mol% Pd(dba)2, 6 mol% tfp) with 4-iodoanisole or tert-
butyl 4-iodobenzoate leading to the arylated products 26a-b in 75-83% yield. After a similar
insertion/cross-coupling sequence, compound 5g afforded the arylated thienothiophene 26c in
74% yield (Scheme 14).
Scheme 14: Magnesium insertion into dichlorothienothiophenes of type 5.
54 a) F. M. Piller, P. Appukkuttan, A. Gavryushin, M. Helm, P. Knochel, Angew. Chem. 2008, 120, 6907; Angew. Chem.
Int. Ed. 2008, 47, 6802; (b) F. M. Piller, A. Metzger, M. A. Schade, B. A. Haag, A. Gavryushin, P. Knochel, Chem.
Eur. J. 2009, 15, 7192.
B. RESULTS AND DISCUSSION FUNCTIONALIZED THIENO[3,2-b]THIOPHENES
21
1.6 Preparation of Fused Pyridazines
Furthermore, new condensed heterocycles were synthesized. The metalation of the
unsubstituted thieno[3,2-b]thiophene (23) with TMPMgCl· LiCl (1, 25 °C, 1 h), followed by a of
Cu(I)-catalyzed acylation reaction with pivaloyl chloride, gave the ketone 27 in 89% yield. When
this compound was treated again with the TMP base 1 (-50 °C, 30 min), the keto-group acted as a
directing group52 and magnesiation occurred regioselectively at the ortho-position. A further
acylation afforded the diketone 28a in 74% yield, which could be condensed with hydrazine
hydrate giving the pyridazine 29a in 95% yield. The repetition of this reaction sequence led to the
fused S-heterocyclic pyridazine derivative 30 in 54% overall yield (Scheme 15).
S
S
t-Bu
S
S
t-Bu
O
O
O
t-Bu
S
SN
N
t-Bu
t-Bu
S
S N
N
t-Bu
t-Bu
N
t-Bu
N
t-Bu
1) TMPMgCl·LiCl (1)
27; 89%
30; 54%
2) CuCN·2 LiClt-BuCOCl
1) TMPMgCl·LiCl (1)
2) CuCN·2 LiClt-BuCOCl
N2H4·H2OEtOH
28a; 74%
29a; 95%
1) TMPMgCl·LiCl (1)
2) CuCN·2 LiCl
t-BuCOCl
3)TMPMgCl·LiCl (1)
4) CuCN·2 LiCl
t-BuCOCl
5) N2H4·H2O, EtOH
S
S
23
Scheme 15: Synthesis of new condensed pyridazine heterocycles.
B. RESULTS AND DISCUSSION FUNCTIONALIZED THIENO[3,2-b]THIOPHENES
22
In an analogous reaction sequence, the diketone 28b was obtained from 27 after metalation
with TMPMgCl· LiCl (1, -50 °C, 30 min) and acylation with 4-chlorobenzoyl chloride. The crude
product was directly condensed with hydrazine hydrate and afforded the pyridazine 29b in 72%
yield (over 2 steps). Similarly, the functionalized thienothiophene 7f was converted to the
pyridazine 29c in 91% yield (Scheme 16). These compounds represent an interesting scaffold as
tailored building-blocks for material applications.
Scheme 16: Synthesis of new fused pyridazine heterocycles.
B. RESULTS AND DISCUSSION FUNCTIONALIZED THIENO[3,2-b]THIOPHENES
23
1.7 Preparation of Thieno[3,2-b]thiophene Oligomers
Finally, small oligomers of polyfunctionalized thienothiophenes were assembled. After
metalation of precursor 31 with TMPMgCl· LiCl (1, 25 °C, 1 h) followed by a Pd-catalyzed cross-
coupling reaction (2.5 mol% Pd(OAc)2, 5.0 mol% S-Phos) with dibromothienothiophene21 32 the
trimer 33a was obtained in 43% yield A Br/Mg-exchange (i-PrMgCl· LiCl,39 -50 °C, 20 min) on
the bromothienothiophenes 34 and 35 afforded the oligomers 33b and 33c after a PEPPSI-iPr
(2.5 mol%) catalyzed cross-coupling reaction55 in 48-51% yield (Scheme 17).
Scheme 17: Synthesis of functionalized oligomers.
55 a) M. G. Organ, S. Avola, I. Dubovyk, N. Hadei, E. A. B. Kantchev, C. J. O’Brien, C. Valente, Chem. Eur. J. 2006,
12, 4749; b)M. G. Organ, S. Calimsiz, M. Sayah, K. H. Hoi, A. J. Lough, Angew. Chem. 2009, 121, 2419; Angew.
Chem. Int. Ed. 2009, 48, 2383.
B. RESULTS AND DISCUSSION FUNCTIONALIZED THIENO[3,2-b]THIOPHENES
24
Deprotonation of 36 using TMPMgCl· LiCl (1, 25 °C, 1 h) and PEPPSI-iPr (2.0 mol%)
catalyzed cross-coupling reaction with dibromothienothiophene 32 gave the trimer 33d in 47%
yield. The oligomer 33e was isolated in 43% yield after a double Br/Li-exchange on compound
32 and cross-coupling (PEPPSI-iPr, 4.0 mol%) with the thienothiophene building block 7g
(Scheme 18).
Scheme 18: Synthesis of functionalized oligomers.
The effect of ring fusion on the electronic absorption and emission properties of
oligothiophenes has been reported in the literature.56 In agreement with these results, the
compounds 33a-e show similar absorption maxima (λmax = 413-416 nm). However, the stability
of the trimers varies widely. While the compounds 33b-d showed extreme sensitivity towards
light and air, the trimeric species of 33a and 33e were found to be stable in air at room
temperature over several weeks. This confirms that the appropriate functionalization of the
thieno[3,2-b]thiophene scaffold allows the preparation of tailored building blocks with specifically
tuned properties for use in material synthesis.
56 a) X. Zhang, A. J. Matzger, J. Org. Chem. 2003, 68, 9813; b) X. Zhang, J. P. Johnson, J. W. Kampf, A. J. Matzger,
Chem. Mater. 2006, 18, 3470.
B. RESULTS AND DISCUSSION FUNCTIONALIZED BENZO[b]THIOPHENES
25
2. BENZO[b]THIOPHENES VIA INTRAMOLECULAR CYCLIZATION
2.1 Precursor Synthesis
The starting materials for the cyclization reaction were obtained from ortho-dihaloarenes.
Depending on the electronic properties of the functional group attached to the aromatic system,
the preparation of these ortho-substituted bromo-iodoarenes differed for electron-poor and
electron-rich systems. For the 3-iodoanisyl- (37) and 3-iodophenol derivatives 38a and 38b
bromination of was achieved using NBS in acetone (0 °C-25 °C, 12 h)57 with remarkable
regioselectivity in 98% yield. The dihaloarenes with electron-withdrawing substituents were
prepared via a halogenation/diazotation sequence of the respective aniline. This route afforded
the 2-bromo-4-chloro-1-iodobenzene 38c from 4-chloroaniline (39) in 79%.58 The cyano- and
ester-substituted analogues 38d-e were isolated in 91% and 73% respectively (Scheme 19).
Scheme 19: Preparation of ortho-substituted dihaloarenes.
These dihaloarenes served as starting materials for I/Mg-exchange reactions39 (i-
PrMgCl· LiCl, -80 °C, 5 min), subsequent transmetalation to zinc and reaction with sulfur
monochloride led to the organic disulfides of type 41. The transformation to the respective
sulfonothioates 42 was carried out according to a literature procedure59 with elemental iodine as
57 B. Andersh, D. L. Murphy, R. J. Olson, Synth. Commun. 2000, 30, 2091.
58 T. Jensen, H. Pedersen, B. Bang-Andersen, R. Madsen, M. Jørgensen, Angew. Chem. Int. Ed. 2008, 47, 888.
59 K. Fujiki, N. Tanifuji, Y. Sasaki, T. Yokoyama, Synthesis 2002, 3, 343.
B. RESULTS AND DISCUSSION FUNCTIONALIZED BENZO[b]THIOPHENES
26
oxidizing agent. These sulfonothioates reacted as electrophiles with metalated alkynes, providing
the desired alkynyl(aryl)thioethers of type 9 and 43 (Scheme 20).
Scheme 20: Reaction sequence towards alkynyl(aryl)thioethers.
The electron-rich TMS-ethynyl(aryl)thioethers 9a and 9b were isolated in 74% and 73%
yield respectively. The electron-deficient analogues 9c-e were obtained in 78-86% return. A
similar reaction starting from commercial 3-bromobenzo[b]thiophene afforded the derivative 9f
in 85% yield (Scheme 21). The regioselective metalation at the 2-position of this scaffold could
be achieved by direct deprotonation, hence a halogenation of this molecule was not necessary.
Scheme 21: TMS-substituted alkynyl(aryl)thioethers of type 9.
Likewise, using the TIPS-protected propargyl alcohol as nucleophilic component gave the
thioethers 43a-d in 72-88% yield.
Scheme 22: TIPS-protected hydroxymethyl-substituted alkynyl(aryl)thioethers of type 43.
B. RESULTS AND DISCUSSION FUNCTIONALIZED BENZO[b]THIOPHENES
27
2.2 Cyclization of TMS-substituted Alkynyl(aryl)thioethers
The metalation of the alkynyl(aryl)thioether 9a was achieved via Br/Mg-exchange using
i-PrMgCl· LiCl,39 and was complete (conversion >95%) within 4 h at 25 °C. Addition of
CuCN· 2 LiCl 49 (30 mol%) facilitated the cyclization towards the benzo[b]thiophene which was
essentially complete at 25 °C after 24 h. However, in the absence of the copper-catalyst no
cyclization was observed. A subsequent acylation with thiophene-2-carbonyl chloride afforded
the 1,2-disubstituted benzo[b]thiophene 12a in 72% yield. (Scheme 23).
Scheme 23: The cyclization/acylation reaction sequence towards functionalized benzo[b]thiophenes.
Correspondingly, after reaction with 4-chlorobenzoyl chloride, the acylated compound 12b
was isolated in 80% return (Table 1, entry 1). Various functionalized alkynyl(aryl)thioethers
underwent a cyclization under similar conditions. Succeeding acylation or allylation reactions (no
further addition of copper was necessary) of the metalated intermediates with a range of acyl
chlorides and allyl bromides afforded the polyfunctional benzothiophenes 12c-s in good to
excellent yields (entries 2-18). Thus, the TIPS-protected phenol 9b gave after a
cyclization/acylation sequence the ketones 12c and 12d in 83% and 87% yield, respectively
(entries 2-3). For the electron-deficient chloroarene 9c, the halogen/magnesium-exchange was
accelerated (25 °C, 1 h) and after completion of the cyclization (25 °C, 26 h), acylation or
allylation reactions led to the functionalized benzo[b]thiophenes 12e-i in 77-96% yield (entries 4-
8). The exchange step on the benzonitrile 9d was undertaken at lower temperature (0 °C, 1 h)
and after cyclization (25 °C, 24 h) and reaction with carbonyl chlorides or ethyl (2-
bromomethyl)acrylate, the products 12j-l were obtained in 80-83% yield (entries 9-11).
B. RESULTS AND DISCUSSION FUNCTIONALIZED BENZO[b]THIOPHENES
28
Table 2: Functionalized benzothiophenes of type 12 obtained after carbomagnesiation of alkynyl(aryl)-thioethers of type 9 and subsequent reaction with electrophiles.
Entry Substrate[a] Electrophile[b] Product
Yield[c]
1
9a
12b; 80%
2
9b
12c; 83%
3
9b
12d; 87%
4
9c
12e; 78%
5
9c
12f; 90%
6
9c
12g; 77%
7
9c
12h; 86%
8
9c
12i; 96%
B. RESULTS AND DISCUSSION FUNCTIONALIZED BENZO[b]THIOPHENES
29
9
9d
12j; 81%
10
9d
12k; 83%
11
9d
12l; 80%
12
9e
12m; 91%
13
9e
12n; 81%
14
9e
12o; 71%
15
9f [d]
H2O
12p; 81%
16
9f [d]
12q; 39%
17
9f [d]
12r; 68%
18
9f [d]
I2
12s; 55% [a] Refer to the experimental section for exact reaction conditions; [b] 0.9 equiv of electrophile was
used; [c] Isolated yield of analytically pure product; [d] Metalation of this substrate was achieved with
TMPMgCl· LiCl.
B. RESULTS AND DISCUSSION FUNCTIONALIZED BENZO[b]THIOPHENES
30
For the more sensitive ester-substituted alkynyl(aryl)thioether 9e the Br/Mg-exchange was
carried out at -25 °C and complete in 1 h. As the cyclization at this temperature was very slow,
and since higher temperatures (>0 °C) led to side reactions of the magnesiated intermediate,
stoichiometric amounts of copper salt were used in this case. The ring-closure was then achieved
by microwave irradiation (50 °C, 100 W) within 1 h. Succeeding acylation or allylation reactions
furnished the expected heterocycles 12m-o in 71-91% yield (entries 12-14).
The scope of this methodology was not limited to arylthioether substrates. Using the
alkynylbenzothiophene 9f allowed the preparation of the related benzo[b]thieno[2,3-d]thiophenes.
Therefore, the thioether 9f was conveniently metalated with TMPMgCl· LiCl20 (25 °C, 2 h) the
ring-closure, however, was more challenging. The formation of a fused 5-membered ring on an
existing 5-membered cycle is much less favored compared to the 6-membered analogue.
Nevertheless, it was achieved with CuCN· 2 LiCl (30 mol%) by microwave irradiation (75 °C,
200 W, 3 h). After quenching, an acylation or allylation reaction, or reaction with I2, the
benzo[b]thieno[3,2-d]thiophenes 12p-s were isolated in 39-81% yield (entries 15-18).
B. RESULTS AND DISCUSSION FUNCTIONALIZED BENZO[b]THIOPHENES
31
2.3 Transformation of the Silyl Protection Group
The TMS-substituted benzothiophenes of type 12 could be converted into the desilylated
compounds using TBAF in THF (25 °C, 1 h). The deprotected benzo[b]thiophenes 13a-g were
generally obtained in high yields of 80-95%. Unfortunately no selectivity for the TMS-group over
the TIPS-group was observed on the phenol derivative 12c, only double deprotection was
achieved resulting in the phenol 13f (Scheme 24).
Scheme 24: Cleavage of the TMS-protection group using TBAF.
B. RESULTS AND DISCUSSION FUNCTIONALIZED BENZO[b]THIOPHENES
32
Alternatively, the TMS-substituent could be transformed into an iodide using iodine
monochloride in dichloromethane (0 °C, 5 min).60 The reaction was complete after addition of
the reagent and the 3-iodobenzothiophene 14a was obtained in 86% yield. Various heteroaryl
iodides (14b-g) were prepared by this method in yields of 73-93%. It is noteworthy, that in this
reaction selectively the TMS-susbtituent was modified, the TIPS-group in compound 14c was left
untouched (Scheme 25).
Scheme 25: Conversion of the TMS-substituent to iodide using iodine monochloride.
60 a) Z. Bo, A. D. Schlüter, J. Org. Chem. 2002, 67, 5327.; b) A. Bossi, S. Maiorana, C. Graiff, A. Tiripicchio, E.
Licandro, Eur. J. Org. Chem. 2007, 4499.
B. RESULTS AND DISCUSSION FUNCTIONALIZED BENZO[b]THIOPHENES
33
2.4 Further Functionalization of the Benzo[b]thiophene Scaffold
Further functionalization of the benzo[b]thiophenes of type 13 was achieved by
deprotonation with TMPMgCl· LiCl (1). Hereby the carbonyl group assisted as directing group52
and the metalation occured regioselectively on the activated benzo[b]thiophene ring. Therefore,
metalation of compound 13b (-30 °C, 3 h) and a copper-catalyzed allylation reaction gave the
highly functionalized heterocycle 15a in 80% yield. Similarly, after metalating 13e under these
conditions, a reaction with ethyl cyanoformate afforded the 2,3-difunctionalized benzothiophene
15b in 78% yield. Direct cross-coupling after transmetalation to zinc was not successful. The
intermediary chelate-stabilized organozinc species proved to be unreactive in such
transformations (Scheme 26).
Scheme 26: Further functionalization of the benzothiophenes via deprotonation.
However, this limitation could be overcome using the iodoarenes of type 14 (Scheme 25).
These valuable intermediates served as electrophiles in cross-coupling reactions. Hence, the alkyl
polyfunctional benzothiophene 16a was obtained after a palladium-catalyzed cross-coupling
reaction of the heterocyclic iodide 14a with (4-acetoxybutyl)zinc bromide43b,61 in 77% yield. A
similar sp3-sp2 cross-coupling with (4-ethoxy-4-oxobutyl)zinc bromide afforded the highly
functionalized compound 16b in 78% yield. Arylzinc reagents54 could be used equally well as
nucleophiles and the arylated benzothiophene 16c and benzothienothiophene 16d were isolated
in 80% and 75% yield, respectively (Scheme 27).
61 T. D. Blümke, F. M. Piller, P. Knochel, Chem. Commun. 2010, 46, 4082.
B. RESULTS AND DISCUSSION FUNCTIONALIZED BENZO[b]THIOPHENES
34
Scheme 27: Functionalization of 3-iodobenzothiophenes via Negishi cross-coupling reactions.
3-Iodobenzothiophenes which do not bear a directing and coordinating carbonyl group in
ortho-position could also be used as the nucleophilic component after an iodine/magnesium-
exchange reaction. The rapid metalation of 14d (i-PrMgCl· LiCl; -78 °C, 5 min) and a subsequent
copper(I)-catalyzed acylation reaction gave the polyfunctional heterocycle 15c in 77% yield.
Similarly, after magnesiation of compound 14f, direct reaction with ethyl cyanoformate afforded
the ester-substituted benzothieno[3,2-b]thiophene 15d in 78% yield (Scheme 28). This pathway is
complementary to the metalation using the TMP-base discussed above (Scheme 26). For
compounds with allyl substituents, direct C-H activation was not successful due to low
conversion, poor regioselectivity and/or polymerization side reactions.
Scheme 28: Functionalization via I/Mg-exchange using i-PrMgCl· LiCl.
B. RESULTS AND DISCUSSION FUNCTIONALIZED BENZO[b]THIOPHENES
35
2.5 Cyclization of TIPS-protected Alkynyl(aryl)thioethers
In the case of the TMS-substituted alkynyl(aryl)thioethers 9a-f (Scheme 21) the addition of
a copper salt was essential for the cyclization step. Interestingly, the alkynyl moiety of substrates
bearing a propargylic group (43a-d) is more susceptible to carbometallation and the cyclization
occurred without addition of a copper catalyst. Substantial amounts of the cyclized form were
detected even before the exchange step was complete. A possible explanation for this is the lower
steric demand of the methylene-group attached to the alkyne compared to the bulky TMS-
susbtituent. Moreover, electronic repulsion of the latter also might rationalize the necessity of a
catalyst facilitating the carbomagnesiation. 37,62
Therefore, when the thioether 43a was treated with i-PrMgCl· LiCl (25 °C), the Br/Mg-
exchange was complete after 5 h and at this point the isomers of open-chain (44) and cyclized
form (45) were detected in 17% to 78%, respectively. As there was no copper catalyst present in
this cyclization step, the succeeding reactions of the magnesium-intermediates allowed a wider
range of electrophiles. Consequently, after completion of the ring-closure (25 °C, 20 h) and
reaction with ethyl cyanoformate, the ester substituted benzo[b]thiophene 46a was obtained in
76% yield (Scheme 29).
Br
S 1) i-PrMgCl·LiClTHF, 25 °C, 25 h
2) EtO2CCN
SCO2Et
MeO MeO
46a; 76%43a
MgCl
SMeO SMeO
MgCl
OTIPSOTIPS
OTIPS
OTIPS
i-PrMgCl·LiClEtO2CCN
44 45
25 °C, 20 h
Scheme 29: Preparation of benzo[b]thiophenes by intramolecular carbomagnesiation
of protected hydroxymethyl-substituted alkynyl(aryl)thioethers of type 43.
Likewise, a copper(I)-catalyzed acylation or palladium-catalyzed cross-coupling reactions
afforded the derived polyfunctional benzothiophenes 46b-d in 55-87% yield respectively (Table
1, entries 1-3). In the case of the electron-poor chloroarene 43b, the exchange reaction was
accelerated (25 °C, 2 h) while the cyclization step was decelerated (25 °C, 24 h) due to the lesser
62 N. Chinkov, D. Tene, I. Marek in Metal-Catalyzed Cross-Coupling Reactions (Ed.: F. Diederich, A. de Meijere), 2nd ed.,
Wiley-VCH, Weinheim, 2004.
B. RESULTS AND DISCUSSION FUNCTIONALIZED BENZO[b]THIOPHENES
36
nucleophilicity or the magnesiated arene. Transmetalation to zinc and subsequent cross-coupling
reactions led to the arylated products 46e-f in 75-84% yield (entries 4-5). The cyclization of the
ester-substituted arene 43c was carried out at lower temperatures (-5 to 0 °C, 52 h) to avoid
decomposition of the sensitive organomagnesium intermediate and the ester-substituted
benzothiophene 46g was obtained in 78% yield (entry 6).
Table 3: Functionalized S-heterocycles of type 46 obtained by carbomagnesiation of protected
hydroxymethyl-substituted alkynyl(aryl)thioethers and subsequent reaction with electrophiles.
Entry Substrate[a] Electrophile[b] Product
Yield[c]
1
43a
46b; 74%
2
43a
46c; 87%
3
43a
46d; 55%
4
43b
46e; 75%
5
43b
46f; 84%
6
43c
H2O
46g; 78%
7
43d [d]
46h; 74%
B. RESULTS AND DISCUSSION FUNCTIONALIZED BENZO[b]THIOPHENES
37
8
43d [d]
EtO2CCN
46i; 54%
9
43d [d]
46j; 57%
10
43d [d]
46k; 37% [a] Refer to the experimental section for exact reaction conditions; [b] 0.9 equiv of electrophile was
used; [c] Isolated yield of analytically pure product; [d] Metalation of this substrate was achieved with
TMPMgCl· LiCl.
As discussed above for the TMS-substituted alkynylthioethers (9; Table 2, entries 15-18),
building a fused 5-membered ring on an existing 5-membered cycle was more challenging and
resulted in comparatively lower yields. The protected hydroxymethyl-substituted
alkynylbenzothiophene 43d was again metalated with TMPMgCl· LiCl (25 °C, 2 h) and the ring
closure was performed without addition of a copper(I) catalyst by microwave irradiation (80 °C,
150 W, 2 h). Subsequent acylation with acid chlorides, direct reaction with ethyl cyanoformate or
cross-coupling with an aryl halide afforded the functionalized benzo[b]thieno[2,3-d]thiophenes
46h-k in 54-74% yield (entries 7-10).
B. RESULTS AND DISCUSSION FUNCTIONALIZED BENZO[b]THIOPHENES
38
2.5 Diversification of Polyfunctional Benzothiophenes to new Heterocyclic Scaffolds
Modification of the benzylic hydroxyl group on the benzothiophenes of type 46, gave
access to new heterocyclic scaffolds. Desilylation of compound 46c (TBAF, 25 °C, 2 h, 47a;
88%) followed by deprotonation of the free alcohol (NaH, THF, 25 °C, 2 h) and succeeding
microwave-assisted nucleophilic aromatic substitution (75 °C, 150 W, 2 h) on the bromoarene led
to the thieno[3,2-c]chromene 48a in 77% yield (overall 68%). This reaction sequence proceeded
smoothly even with the electron-rich anisyl arene 46e affording 48b in 79% yield (overall 71%).
Alternatively, after desilylation of compound 46b (TBAF, 25 °C, 1 h, 47c; 82%), the alcohol
moiety was oxidized to the aldehyde with DMP and condensation with hydrazine hydrate
furnished the thieno[2,3-d]pyridazine 48c in 90% yield (overall 74%).
Scheme 30: Preparation of new heterocyclic scaffolds.
B. RESULTS AND DISCUSSION SOLID ORGANOZINC REAGENTS
39
3. PREPARATION AND REACTIONS OF SOLID ORGANOZINC
REAGENTS
3.1 Preparation of Solid Salt-Stabilized Functionalized Organozinc Reagents
The solid salt-stabilized functionalized aryl, heteroaryl and benzylic zinc reagents were
readily prepared in a one-pot procedure in which the organic bromide or chloride was treated
with magnesium turnings (2.5 equiv) and the THF soluble salt Zn(OPiv)2· 2 LiCl (1.5 equiv).
Under these conditions, a fast formation of the zinc reagent was observed at 25 °C within 2 h.63
The presence of Zn(OPiv)2· 2 LiCl not only stabilized the resulting zinc reagent, but also
accelerated its formation which was essential for tolerating sensitive functional groups. After
evaporation of the solvent, this methodology gave access to the solid zinc reagents 18a-i in 59-
81% yield bearing electron-donating or electron-withdrawing substituents. They were obtained as
convenient powders in contrast to regular zinc reagents which produced only highly viscous oils
when the solvent was removed.
Scheme 31: Preparation of solid organozinc reagents; [a] Complexed Mg(OPiv)X (X = Br, Cl) and
LiCl are omitted for clarity; [b] Prepared by I/Mg- or Br/Mg-exchange with i-PrMgCl· LiCl and
transmetalation with Zn(OPiv)2· 2 LiCl.63,64
63 S. Bernhardt, G. Manolikakes, T. Kunz, P. Knochel, Angew. Chem. 2011, 123, 9372; Angew. Chem. Int. Ed. 2011, 50,
9205.
64 These experiments were preformed by S. Bernhardt and are given here for completeness (cf. Ref. 63).
B. RESULTS AND DISCUSSION SOLID ORGANOZINC REAGENTS
40
Although the ester and nitrile substituted zinc reagents 18e and 18f were prepared in
satisfactory yields (59-64%) by direct insertion, an improvement has been achieved via an I/Mg-
or Br/Mg-exchange with i-PrMgCl·LiCl followed by a transmetalation with Zn(OPiv)2· 2 LiCl
(72-89%).64,65
3.2 Application in Negishi Cross-Coupling Reactions
The organozincs of type 18 underwent Negishi cross-couplings under very mild conditions
using PEPPSI-iPr (2 mol%) as catalyst. Thus, the reaction of a THF solution of the arylzinc
pivalate 18f with methyl 4-bromobenzoate led to the biaryl cross-coupling product 19a (25 °C,
2 h) in 81% yield (Scheme 32).
Scheme 32: Palladium-catalyzed Negishi cross-coupling of organozinc reagents of type 18.
The reaction scope of Negishi cross-couplings with arylzinc pivalates 18a-i using various
functionalized aryl and heteroaryl bromides and chlorides is very broad. The uniformly fast
reactions (2 h) were performed at 25 °C and the expected products were obtained in high yields
(66-99%). The cross-coupling reaction of the arylzinc reagents 18b and 18c with (2-
bromophenyl)(morpholino)methanone afforded the amides 19b and 19c in 88% and 80% yield,
respectively (Table 4, entries 1-2). The presence of an unprotected amine function in the aryl
bromides could be tolerated, and the arylated aminobenzonitrile 19d and the aminobenzoates 19e
and 19f were isolated in 66-79% yield (entries 3-5). Moreover, heterocyclic electrophiles were
smoothly arylated, and the quinoline and indole derivatives 19g and 19h were obtained in 99%
and 91% (entries 6-7). The heteroaryl zinc pivalate 18i also reacted under mild conditions with 2-
chloropyrazine giving the heterocyclic biaryl compound 19i in 94% yield (entry 8).
65 The content of active zinc species was determined by titration with a 1.0 M solution of iodine in THF. For the
halogen-magnesium exchanges with i-PrMgCl· LiCl, ethyl 4-iodobenzoate and 4-bromobenzonitrile were used.
B. RESULTS AND DISCUSSION SOLID ORGANOZINC REAGENTS
41
Table 4: PEPPSI-iPr catalyzed cross-couplings of aromatic zinc pivalates of type 18.
Entry Arylzinc Reagent Electrophile[a] Product, Yield[b]
1
18b
19b; 88%
2
18c
19c; 80%
3
18d
Br
H2N
CN
19d; 79%
4
18e
19e; 69%
5
18g
19f; 66%
6
18d
19g; 99%
7
18e
19h; 91%
8
18i
19i; 94%
[a] 0.84 equiv of electrophile was used. [b] Isolated yield of analytically pure product.
B. RESULTS AND DISCUSSION SOLID ORGANOZINC REAGENTS
42
Interestingly, these cross-coupling reactions could be performed in different solvents.
Hence, using technical grade ethyl acetate66 as solvent, the cross-coupling of the benzylic
organozinc pivalate 18h with 4-chlorobenzophenone provided compound 19j in 93% yield
compared to 73% when THF was used as solvent. Changing the catalyst system to palladium(II)
acetate and S-Phos resulted in a comparative yield of 71% (Scheme 33).
Scheme 33: Cross-coupling reactions with varying solvents and catalyst-systems.
66 Ethyl acetate was purchased from Sigma-Aldrich with a purity of 99 % and was used without drying or destillation
prior to use.
B. RESULTS AND DISCUSSION SOLID ORGANOZINC REAGENTS
43
3.3 Reactivity-Tuning of Organozinc Reagents
Recently, it has been shown that MgCl2 greatly enhances the reactivity of organozinc
reagents towards carbonyl derivatives.44g Moreover both, MgCl2 and LiCl,67 increase the intrinsic
reactivity of organozinc reagents by enhancing their nucleophilicity as well as the electrophilicity
of the carbonyl compound (Lewis acid activation).68 This activation was also observed for
arylzinc pivalates of type 18. Therefore, the reaction of the arylzinc pivalate 18a with 2-
bromobenzaldehyde rapidly gave the benzhydryl alcohol 49 in 72% yield69 due to the complexed
magnesium salts in reagent 18a. This salt effect could be overcome by the addition of the
powerful Pd-catalyst PEPPSI-iPr (2 mol%). In the presence of this catalyst the formyl group of
2-bromobenzaldehyde was left untouched and the Negishi cross-coupling product 19k was
obtained in 82% yield (Scheme 34).
Scheme 34: Tunable reactivity of organozinc reagents of type 18 in the presence or absence of PEPPSI-iPr.
67 D. R. Armstrong, W. Clegg, P. García-Álvarez, A. R. Kennedy, M. D. McCall, L. Russo, E. Hevia, Chem. Eur. J.
2011, 17, 8333.
68 a) E. Hevia, J. Z. Chua, P. García-Álvarez, A. R. Kennedy, M. D. McCall, Proc. Nat. Acd. Sci. USA 2010, 107, 5249.
b) D. R. Amstrong, W. Clegg, P. García-Álvarez, M. D. McCall, L. Nuttall, A. R. Kennedy, L. Russo, E. Hevia,
Chem. Eur. J. 2011, 17, 4470; c) D. R. Amstrong, P. García-Álvarez, A. R. Kennedy, R. E. Mulvey, J. A. Parkinson,
Angew. Chem. 2010, 122, 3253; Angew. Chem. Int. Ed. 2010, 49, 3185; d) E. Hevia, R. Mulvey, Angew. Chem. 2011, 123,
6576; Angew. Chem. Int. Ed. 2011, 50, 6448; e) J. G. Kim, P. J. Walsh, Angew. Chem. 2006, 118, 4281; Angew. Chem.
Int. Ed. 2006, 45, 4175; f) L. Salvi, J. G. Kim, P. J. Walsh, J. Am. Chem. Soc. 2009, 131, 12483.
69 The carbonyl addition experiment was preformed by S. Bernhardt and is given for completeness (cf. ref. 63).
B. RESULTS AND DISCUSSION SUMMARY
44
4. SUMMARY
4.1 Functionalization of Thieno[3,2-b]thiophene
A full functionalization of all four positions of the thieno[3,2-b]thiophene scaffold was
achieved. Starting from 2,5-dichlorothieno[3,2-b]thiophene, magnesiation of the 3- and 6-position
using TMPMgCl· LiCl furnished, after trapping with various electrophiles, 3,6-difunctionalized
2,5-dichlorothieno[3,2-b]thiophenes (Scheme 35).
Scheme 35: 3,6-Difunctionalized 2,5-dichlorothieno[3,2-b]thiophenes.
Subsequent dechlorination and regioselective metalation or regioselective magnesium
insertion into the C-Cl bond provided polyfunctionalized thieno[3,2-b]thiophenes that so far have
not been accessible. A large variety of functional groups could be introduced as substituents and
were tolerated in succeeding transformations (Scheme 36).
Scheme 36: Fully functionalized thieno[3,2-b]thiophenes.
B. RESULTS AND DISCUSSION SUMMARY
45
This methodology allows the fine-tuning of material properties of such heterocycles (e.g
absorption band, overlap of frontier orbitals) by introducing specific side chains in monomeric
building-blocks as could be shown in the oligomer synthesis (Scheme 37).
Scheme 37: Synthesis of functionalized oligomers.
The condensation reaction of diketones with hydrazine hydrate led to fused pyridazine
derivatives. These compounds represent a new class of sulfur- and nitrogen-containing
heterocycles that will also be of interest as new materials (Scheme 38).
Scheme 38: Fused pyridazine derivatives.
B. RESULTS AND DISCUSSION SUMMARY
46
4.2 Benzo[b]thiophenes via Intramolecular Carbomagnesiation
A novel copper(I)-catalyzed intramolecular carbomagnesiation procedure has been
developed. This methodology allowed the preparation of magnesiated S-heterocycles from
alkynyl(aryl)thioethers and their reaction with various electrophiles gave access to 2,3-
difunctionalized benzo[2,3-b]thiophenes (Scheme 39).
Scheme 39: Preparation of benzo[b]thiophenes by a copper-catalyzed carbomagnesiation of alkynylthioethers.
The mild conditions of this method were compatible with a wide range of functional
groups. Further transformations of these compounds led to highly functionalized benzo[b]-
thiophene derivatives (Scheme 40).
Scheme 40: Preparation of polyfunctional benzo[b]thiophenes.
B. RESULTS AND DISCUSSION SUMMARY
47
For activated alkynyl moieties the carbometallation step did not require the addition of a
Cu(I) salt and the cyclization occurred at ambient temperature. Subsequent modifications of the
cyclization products afforded highly diversified benzothiophene derivatives and new heterocyclic
scaffolds (Scheme 41).
Scheme 41: Diversification of benzo[b]thiophenes affording new heterocyclic scaffolds.
The related benzothienothiophenes were also prepared by this protocol. Metalation of the
benzothiophene substrate was undertaken with TMPMgCl· LiCl and cyclization was achieved by
microwave irradiation. Subsequent reactions with electrophiles gave 2,3-disubstituted
benzothienothiophenes (Scheme 42).
Scheme 42: Preparation of the related benzo[b]thieno[2,3-d]thiophenes.
An extension of this methodology to heteroarene thioether substrates and to the synthesis
of functionalized indoles seems feasible.
B. RESULTS AND DISCUSSION SUMMARY
48
4.3 Preparation and Reactions of Solid Functionalized Organozinc Reagents
The preparation of solid aryl, heteroaryl and benzylic zinc reagents was achieved through
stabilization with the organic pivalate anion. Starting from the corresponding aryl- and
heteroraryl bromides and benzylic chlorides these organozinc pivalates were available in a one-
pot procedure under mild conditions using Mg and Zn(OPiv)2· 2 LiCl. Removal of the solvent
afforded convenient powders which showed excellent reactivity in Negishi cross-coupling
procedures (Scheme 43).
Scheme 43: Preparation and reactions of solid organozinc reagents.
Furthermore, the reactivity of these organozinc reagents could be influenced depending on
the reaction conditions. In the absence of a cross-coupling catalyst, these activated zinc reagents
underwent carbonyl addition reactions. However, in the presence of the PEPPSI-iPr catalyst,
smooth cross-coupling reactions were achieved (Scheme 44).
Scheme 44: Tuneable reactivity of organozinc reagents in the presence or absence of PEPPSI-iPr.
Moreover, this robust methodology allowed the use of different catalytic systems and the
cross-coupling reactions could also be carried out in technical grade ethyl acetate as solvent.
C. EXPERIMENTAL SECTION
C. EXPERIMENTAL SECTION GENERAL CONSIDERATIONS
50
1. GENERAL CONSIDERATIONS
All reactions were carried out under argon atmosphere in glassware dried with a heat gun.
Syringes which were used to transfer anhydrous solvents or reagents were purged with argon or
nitrogen prior to use. Indicated yields are isolated yields of compounds estimated to be >95%
pure as determined by 1H-NMR (25 °C) and capillary GC. Column chromatography was
performed using SiO2 (0.040 – 0.063 mm, 230 – 400 mesh ASTM) from Merck. Magnesium
turnings (> 99.5%), magnesium powder (> 99%) and zinc dust (> 90%) were obtained from
Riedel-de Haën. CuCN, ZnCl2 and LiCl were obtained from Fluka. The given Watt-numbers
refer to the maximum magnetron power output of the microwave.
1.1 Solvents
Solvents were dried according to standard procedures by distillation over drying agents and
stored under argon.
CH2Cl2 was predried over CaCl2 and distilled from CaH2.
DMF was heated to reflux for 14 h over CaH2 and distilled from CaH2.
EtOH was treated with phthalic anhydride (25 g/L) and sodium, heated to reflux for 6 h and
distilled.
Et2O was predried over calcium hydride and dried with the solvent purification system SPS-400-
2 from INNOVATIVE TECHNOLOGIES INC.
NMP was heated to reflux for 14 h over CaH2 and distilled from CaH2.
Pyridine was dried over KOH and distilled.
THF was continuously refluxed and freshly distilled from sodium benzophenone ketyl under
nitrogen.
Toluene was predried over CaCl2 and distilled from CaH2.
NEt3 was dried over KOH and distilled.
Solvents for column chromatography were distilled on a rotary evaporator prior to use.
C. EXPERIMENTAL SECTION GENERAL CONSIDERATIONS
51
1.2 Reagents
All reagents were obtained from commercial sources and used without further purification unless
otherwise stated. Liquid reagents were distilled prior to use.
i-PrMgCl· LiCl solution in THF was purchased from Chemetall.
n-BuLi solution in hexane was purchased from Chemetall.
TMPMgCl· LiCl was prepared according to a literature procedure.20
CuCN· 2 LiCl solution (1.00 M) was prepared by drying CuCN (80.0 mmol, 7.17 g) and LiCl
(160 mmol, 6.77 g) in a Schlenk tube under vacuum at 140 °C for 5 h. After cooling, 80 mL dry
THF were added and stirring was continued until the salts were dissolved.
ZnCl2 solution (1.00 M) was prepared by drying ZnCl2 (100 mmol, 136 g) in a Schlenk tube under
vacuum at 140 °C for 5 h. After cooling, 100 mL dry THF were added and stirring was continued
until the salt was dissolved.
Zn(OPiv)2· 2 LiCl: Pivalic acid (20.4 g, 22.6 mL, 200 mmol) was placed in a dry and argon-
flushed Schlenk-flask, equipped with a magnetic stirring bar and a septum, and dissolved in dry
THF (100 mL). The solution was cooled to 0 °C and methyllithium (135 mL, 1.63 M in diethyl
ether, 220 mmol) was added dropwise over a period of 45 min. ZnCl2 (100 mL, 1.0 M in THF,
100 mmol) was added and the mixture was stirred for 2 h at 25 °C. The solvent was removed in
vacuo and Zn(OPiv)2· 2 LiCl was obtained as a colourless solid in quantitative yield.
1.3 Content Determination of Organometallic Reagents
Organozinc and organomagnesium reagents were titrated with I2 in a 0.5 M LiCl solution in
THF.
Organolithium reagents were titrated with dry 2-propanol against 1,10-phenanthroline in THF.
TMPMgCl· LiCl, was titrated with benzoic acid against 4-(phenylazo)diphenylamine in THF.
C. EXPERIMENTAL SECTION GENERAL CONSIDERATIONS
52
1.4 Analytical data
1H-NMR and 13C-NMR spectra were recorded on VARIAN Mercury 200, BRUKER ARX 300,
VARIAN VXR 400 S and BRUKER AMX 600 instruments. Chemical shifts are reported as δ-
values in ppm relative to teramethylsilane. The following abbreviations were used to characterize
signal multiplicities: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) as well as br
(broadened).
Mass spectroscopy: High resolution (HRMS) and low resolution (MS) spectra were recorded on
a FINNIGAN MAT 95Q instrument. Electron impact ionization (EI) was conducted with an
ionization energy of 70 eV.
For coupled gas chromatography/mass spectrometry, a HEWLETT-PACKARD HP 6890/MSD
5973 GC/MS system was used. Molecular fragments are reported starting at a relative intensity
of 10%.
Infrared spectra (IR) were recorded from 4500 cm-1 to 650 cm-1 on a PERKIN ELMER
Spectrum BX-59343 instrument. For detection a SMITHS DETECTION DuraSamplIR II
Diamond ATR sensor was used. Wavenumbers are reported in cm-1 starting at an absorption of
10%.
Melting points (mp) were determined on a BÜCHI B-540 melting point apparatus and are
uncorrected.
C. EXPERIMENTAL SECTION TYPICAL PROCEDURES
53
2. TYPICAL PROCEDURES
Typical Procedure for the Deprotonation using TMPMgCl· LiCl (TP1):
A dry and argon flushed Schlenk-flask, equipped with a magnetic stirrer and a septum was
charged with the starting material in THF (0.1-1.0 M solution) and cooled to the appropriate
temperature. TMPMgCl· LiCl was added dropwise and the reaction mixture stirred for the
indicated time (the completion of the reaction was checked by GC analysis of reaction aliquots
quenched with a solution of I2 in THF).
Typical Procedure for the Magnesium Insertion in the Presence of ZnCl2 (TP2):
A dry and argon-flushed Schlenk-flask, equipped with a magnetic stirrer and a septum, was
charged with LiCl (160 mg, 3.75 mmol) and magnesium turnings (182 mg, 7.5 mmol) and was
heated under vacuum until dry. ZnCl2 solution (3.3 mL, 3.3 mmol) and THF (6 mL) were added
and the magnesium was activated with DIBAL-H (0.3 mL, 0.1 M in THF, 0.03 mmol). After
5 min of stirring the aryl halide (3.0 mmol) was added in one portion at 25 °C. The reaction
mixture was stirred for the indicated time and then canulated to a new Schlenk-flask for the
reaction with an electrophile.
Typical Procedure for Cross-coupling Reactions (TP3):
To the freshly prepared magnesium reagent was added ZnCl2 (1.0 M in THF, 1.1 equiv) and the
reaction mixture was stirred for 15 min at the indicated temperature. The catalytic system and the
aryl halide were added and the reaction mixture was warmed to 25 °C. After stirring for the
indicated time the reaction mixture was quenched with half concentrated aqueous NH4Cl
solution, extracted three times with Et2O, dried (Na2SO4) and concentrated in vacuo. The crude
residue was purified by flash column chromatography on silica gel.
Typical Procedure for Allylation or Acylation Reactions (TP4):
To the freshly prepared magnesium reagent was added CuCN· 2 LiCl (1.0 M in THF, 20 mol%)
and the reaction mixture was stirred for 15 min at the indicated temperature. The allyl bromide or
acyl chloride was added and the reaction mixture was stirred for the indicated time at the
respective temperature. The reaction was quenched with half concentrated aqueous NH4Cl
solution, extracted three times with Et2O, dried (Na2SO4) and concentrated in vacuo. The crude
residue was purified by flash column chromatography on silica gel.
C. EXPERIMENTAL SECTION TYPICAL PROCEDURES
54
Typical Procedure for Dechlorination Reactions (TP5):
A microwave vial equipped with a stirring bar was charged with the 2,5-dichlorothienothiophene
in EtOH. Pd/C (10% Pd, 50% wet with water) and NH4HCO2 were added and the reaction
mixture was heated using a Biotage Initiator 2.5 system (120 °C, 100 W, 1 h). The mixture was
allowed to cool to 25 °C, another portion of Pd/C was added and the mixture was again heated.
This procedure was repeated for the indicated time. After the last reaction cycle the mixture was
allowed to cool to 25 °C and filtered through Celite®. The crude residue was purified by flash
column chromatography on silica gel.
Typical Procedure for Halogen/Magnesium-Exchange Reactions (TP6):
A dry and argon flushed Schlenk-flask, equipped with a magnetic stirrer and a septum was
charged with the starting aryl bromide in THF (approx. 1.0 M solution) and cooled to the
indcated temperature. Then i-PrMgCl· LiCl was added and the reaction was stirred for the
indicated time (the completion of the reaction was checked by GC analysis of reaction aliquots
quenched with half concentrated aqueous NH4Cl solution).
Preparation of Electron Rich Dihalogen-Compounds (TP7):
The electron rich iodo-compounds were brominated according to a literature procedure.70
Preparation of Electron Poor Dihalogen-Compounds via diazotation (TP8):
The respective substituted aniline was dissolved in chloroform (0.5 M) and cooled to 0 °C. NBS
(1.01 equiv) was added in one portion and the reaction mixture was stirred for 3 h at that
temperature. The crude mixture was washed with water (3x), dried (MgSO4) and the solvent
evaporated in vacuo. The crude bromoaniline was suspended in a mixture of concentrated sulfuric
acid and water (1:2) and cooled to 0 °C. A solution of NaNO2 (1.05 equiv, 2 M in water) was
added dropwise over 1 h and the resulting mixture stirred further for 1 h at 0 °C. Then CuI
(5 mol%) was added in one portion and following a solution of KI (1.10 equiv, 2 M in water) was
added dropwise over one hour. The resulting sluggish reaction mixture was stirred over night
while warming to room temperature. The solids were dissolved in CH2Cl2, separated from the
aqueous phase, then washed with brine and sodium thiosulfate solution and dried (MgSO4). After
removal of the solvent in vacuo, the crude product was purified by flash column chromatography
on silica gel.
70 B. Andersh, D. L. Murphy, R. J. Olson, Synth. Commun. 2000, 30, 2091.
C. EXPERIMENTAL SECTION TYPICAL PROCEDURES
55
Preparation of Organic Disulfides (TP9):
The aryl disulfides were prepared according to a literature procedure71 whereby the
iodine/magnesium-exchange was uniformly carried out at -80 °C and after transmetalation to
zinc S2Cl2 (0.48 equiv) was added. The crude products were used without further purification in
the sulfonothioate synthesis. Yield and analytical data of new compounds, however, were taken
from purified samples.
Preparation of Sulfonothioates (TP10):
The sulfonothioates were prepared according to a literature procedure.72 To a mixture of sodium
benzenesulfinate (3.2 equiv) and the organic disulfide (1.0 equiv) in CH2Cl2 (0.1 m) was added I2
(2.0 equiv) in one portion. The resulting suspension was stirred until the disulfide was consumed
(checked by TLC, 12-72 h). Then CH2Cl2 (100 mL) was added and the crude reaction mixture
was washed with aq. sat. Na2S2O3 until the color of iodine disappeared. The organic layer was
washed with water, dried (MgSO4) and the solvent was evaporated. The crude products were
purified by flash column chromatography on silica gel.
Typical Procedure for the Preparation of Alkynyl(aryl)thioethers (TP11):
A dry and argon flushed Schlenk-flask, equipped with a magnetic stirrer and a septum was
charged with the terminal alkyne (1.00-1.50 equiv) in THF (approx. 1.0 M solution) and cooled to
-30 °C. Then i-PrMgCl· LiCl (1.00-1.20 equiv) was added and the reaction was stirred for 30 min
at this temperature before a solution of the sulfonothioate in THF (approx. 0.5 M solution) was
added dropwise at -50 °C. The sluggish mixture was stirred for 1-6 h while warming to room
temperature. The reaction was quenched with half concentrated aqueous NH4Cl solution,
extracted three times with Et2O, the organic layers dried (MgSO4) and concentrated in vacuo. The
crude residue was purified by flash column chromatography on silica gel.
Typical Procedure for the Copper-Catalyzed Carbomagnesiation Reaction (TP12):
Succeeding the typical procedure for halogen/magnesium-exchange (TP6) or for deprotonation
(TP7) CuCN· 2 LiCl solution (1.0 M in THF, 30-100 mol%) was added to the reaction mixture at
the indicated temperature and stirred for the indicated time (the completion of the reaction was
checked by GC analysis of reaction aliquots quenched with half concentrated aqueous NH4Cl
71 T. J. Korn, P. Knochel, Synlett 2005, 7, 1185.
72 K. Fujiki, N. Tanifuji, Y. Sasaki, T. Yokoyama, Synthesis 2002, 3, 343.
C. EXPERIMENTAL SECTION TYPICAL PROCEDURES
56
solution; typically two peaks with slightly differing retention time could be detected,
corresponding to the open-chain and cyclized form).
Typical Procedure for Microwave-Assisted Reactions (TP13):
Microwave assisted reactions were carried out using a Biotage Initiator 2.5 system. The reaction
mixture was therefore transferred into a dry and argon flushed microwave vial equipped with a
stirring bar and septum pressure-cap. The reaction parameters (temperature, max. magnetron
output, time) are given for the respective substance.
Typical Procedure for the Removal of Silyl-Protection Groups (TP14):
To the respective silyl-substituted compound (approx. 0.1 M in THF) was added TBAF trihydrate
(1.2-2.0 equiv) at 25 °C and the mixture was stirred until the starting material was consumed (1-
12 h). The solvent was evaporated in vacuo and the crude residue purified by flash column
chromatography on silica gel.
Typical Procedure for the Conversion of the TMS-Group to Iodide (TP15):
To the respective TMS-substituted compound (approx. 0.2 M in CH2Cl2) was added iodine
monochloride ICl (1.1 equiv) at 0 °C and the mixture was stirred for 5 min. The reaction was
quenched with sodium thiosulfate solution, extracted three times with CH2Cl2, the organic layers
dried (MgSO4) and concentrated in vacuo. The crude residue was purified by flash column
chromatography on silica gel.
Typical Procedure for the Preparation of Organozinc Pivalates of Type 18 by Magnesium
Insertion in the Presence of Zn(OPiv)2· 2 LiCl (TP16):
Zn(OPiv)2· 2 LiCl was placed in a Schlenk-flask, equipped with a magnetic stirrer and a septum,
dried for 5 min at 400 °C (heat gun) in high vacuum and then dissolved in dry THF. The organic
halide (1.00 equiv) was added and the mixture was stirred for 2 min at room temperature.
Magnesium turnings (2.50 equiv) were added and the Schlenk-flask was placed in a water bath for
cooling during the initial heat evolution of the insertion reaction. The reaction mixture was
stirred for the given time until GC analysis of a quenched reaction aliquot showed complete
conversion. Then, the supernatant solution was carefully cannulated to a new dry and argon-
flushed Schlenk-flask via syringe filter and the solvent was removed in vacuo.
C. EXPERIMENTAL SECTION TYPICAL PROCEDURES
57
Typical Procedure for the Preparation of Organozinc Pivalates of Type 18 by
Halogen/Magnesium-Exchange and Transmetalation (TP17):
In a dry and argon-flushed Schlenk-flask, equipped with a magnetic stirrer and a septum, the
organic halide was dissolved in dry THF. i-PrMgCl· LiCl was added dropwise at the given
temperature and the reaction mixture was stirred for the given time at this temperature until GC
analysis of a quenched reaction aliquot showed complete conversion. A solution of
Zn(OPiv)2· 2 LiCl (the zinc salt was dried for 5 min at 400 °C in high vacuum and then dissolved
in dry THF (0.5 M)) was added dropwise and the mixture was stirred for 30 min at the given
temperature. Then the solvent was removed in vacuo.
Typical Procedure for Pd-Catalyzed Cross-Coupling Reactions of Organozinc Pivalates
of Type 18 (TP18):
In a dry and argon-flushed Schlenk-flask, equipped with a magnetic stirring bar and a septum, the
solid organozinc reagent was dissolved in the solvent of choice. The organic halide (0.84 equiv)
was added followed by PEPPSI-iPr (2 mol%) and the mixture was stirred for the given time at
the given temperature. Then sat. aq. NH4Cl (10 mL) was added and the aqueous layer was
extracted with diethyl ether (3 × 20 mL). The combined organic phases were dried (Na2SO4) and
concentrated in vacuo. The crude residue was purified by flash column chromatography on silica
gel.
Typical Procedure for the Addition of Organozinc Pivalates of Type 18 to Carbonyl
Derivatives (TP19):
In a dry and argon-flushed Schlenk-flask, equipped with a magnetic stirring bar and a septum, the
solid organozinc reagent was dissolved in dry THF. The carbonyl derivative (0.84 equiv) was
added and the mixture was stirred for the given time at the given temperature. Then sat. aq.
NH4Cl (10 mL) was added and the aqueous layer was extracted with diethyl ether (3 × 20 mL).
The combined organic phases were dried (Na2SO4) and concentrated in vacuo. The crude residue
was purified by flash column chromatography on silica gel.
C. EXPERIMENTAL SECTION
58
3. PRODUCT SYNTHESIS AND ANALYTICAL DATA
3.1 Functionalization of Thieno[3,2-b]thiophene
Preparation of 3,6-Disubstituted 2,5-Dichlorothieno[3,2-b]thiophenes
2,5-Dichlorothieno[3,2-b]thiophene (2)
Thieno[3,2-b]thiophene73 (5.61 g, 40 mmol) was dissolved in DMF (80 mL) at room temperature.
N-Chlorosuccinimide (10.68 g, 80 mmol) was added and the reaction mixture stirred for 6 h.
Water was added and the mixture extracted three times with ether. The organic phase was
washed 4 times with water, dried (MgSO4) and concentrated in vacuo. Flash column
chromatographical purification on silica gel (pentane) afforded 2 (8.29 g, 99%) as a white solid.
Mp. : 99.1-101.0 °C. 1H-NMR (C6D6, 300 MHz): δ = 6.19 (s, 2H). 13C-NMR (C6D6, 75 MHz): δ = 134.7, 130.8, 118.9.
IR (Diamond ATR, neat): ν~ = 3094 (w), 1622 (w), 1459 (m), 1447 (m), 1337 (m), 1324 (w),
1271 (w), 1160 (m), 1104 (w), 1030 (s), 1001 (w), 967 (w), 862 (s), 839 (m), 808 (vs), 750 (w), 653
(w).
MS (EI, 70 eV): m/z = 208 (100) [M+], 173 (48), 129 (11), 97 (11), 69 (20), 44 (18).
HR-MS: (C6H2Cl2S2) calculated: 207.8975 found: 207.8969.
2,5-Dichloro-3-(methylthio)thieno[3,2-b]thiophene (4a)
Prepared according to TP1 from 2 (4.18 g, 20.0 mmol) and TMPMgCl· LiCl (19.1 mL, 1.15 M in
THF, 22.0 mmol). Deprotonation time: 45 min at 25 °C. PhSO2SMe (4.52 g, 24.0 mmol) was
73 Thieno[3,2-b]thiophene and 3-bromothieno[3,2-b]thiophene were prepared according to a method described by
Matzger et al. Analytical data was found to match literature data. T. J. Henssler, A. J. Matzger, Org. Lett. 2009, 11,
3144.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
59
added at 0 °C and the reaction mixture stirred for 30 min while warming to room temperature.
The reaction mixture was quenched with half concentrated aqueous NH4Cl solution, extracted
three times with Et2O, dried (MgSO4) and concentrated in vacuo. Flash column chromatographical
purification on silica gel (pentane) afforded 4a (4.90 g, 96%) as a white solid.
Mp. : 40.2-44.1 °C. 1H-NMR (CDCl3, 300 MHz): δ = 7.05 (s, 1H), 2.46 (s, 3H). 13C-NMR (CDCl3, 75 MHz): δ = 138.4, 132.0, 131.6, 131.5, 123.4, 119.3, 17.2.
IR (Diamond ATR, neat): ν~ = 3091 (w), 2922 (m), 1486 (m), 1442 (s), 1412 (s), 1330 (m),
1325 (m), 1307 (m), 1160 (m), 1153 (m), 1057 (s), 997 (m), 975 (m), 963 (m), 900 (vs), 854 (s), 833
(m), 799 (vs), 733 (w).
MS (EI, 70 eV): m/z = 254 (100) [M+], 241 (66), 239 (90), 204 (15).
HR-MS: (C7H4Cl2S3) calculated: 253.8852 found: 253.8845.
2,5-Dichloro-3-(phenylthio)thieno[3,2-b]thiophene (4b)
Prepared according to TP1 from 2 (1.05 g, 5.0 mmol) and TMPMgCl· LiCl (5.8 mL, 0.95 M in
THF, 22.0 mmol). Deprotonation time: 45 min at 25 °C. PhSO2SPh (4.52 g, 24.0 mmol) was
added at 0 °C and the reaction mixture stirred for 30 min while warming to room temperature.
The reaction mixture was quenched with half concentrated aqueous NH4Cl solution, extracted
three times with Et2O, dried (MgSO4) and concentrated in vacuo. Flash column chromatographical
purification on silica gel (pentane) afforded 4b (1.35 g, 85%) as a white solid.
Mp. : 78.0-79.2 °C. 1H-NMR (C6D6, 300 MHz): δ = 7.10 (m, 2H), 6.78 (m, 3H), 6.07 (s, 1H). 13C-NMR (C6D6, 75 MHz): δ = 138.1, 133.0, 132.6, 132.2, 131.9, 130.4, 129.4, 127.6, 122.0,
119.2.
IR (Diamond ATR, neat): ν~ = 1580 (w), 1477 (m), 1444 (m), 1154 (w), 1059 (m), 1024 (w),
909 (m), 853 (w), 806 (s), 734 (vs), 686 (s).
MS (EI, 70 eV): m/z = 316 (50) [M+], 281 (18), 246 (100), 123 (14).
HR-MS: (C12H6Cl2S3) calculated: 315.9009 found: 315.9004.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
60
(2,5-Dichlorothieno[3,2-b]thiophen-3-yl)trimethylsilane (4c)
Prepared according to TP1 from 2 (1.05 g, 5.0 mmol) and TMPMgCl· LiCl (4.8 mL, 1.15 M in
THF, 5.5 mmol). Deprotonation time: 45 min at 25 °C. TMSCN (595 mg, 6.0 mmol) was added
at -80 °C and the reaction mixture stirred for 2 h while warming to room temperature. The
reaction mixture was quenched with half concentrated aqueous NH4Cl solution, extracted three
times with Et2O, dried (MgSO4) and concentrated in vacuo. Flash column chromatographical
purification on silica gel (pentane) afforded 4c (1.20 g, 85%) as a colorless oil. 1H-NMR (C6D6, 300 MHz): δ = 6.31 (s, 1H), 0.27 (s, 9H). 13C-NMR (C6D6, 75 MHz): δ = 140.5, 136.6, 134.8, 130.4, 130.2, 118.5, 0.9.
IR (Diamond ATR, neat): ν~ = 2955 (w), 1487 (m), 1437 (s), 1401 (m), 1277 (m), 1250 (vs),
1155 (m), 1048 (vs), 890 (s), 838 (vs), 759 (vs), 707 (s).
MS (EI, 70 eV): m/z = 280 (75) [M+], 265 (80), 187 (100), 93 (14).
HR-MS: (C9H10Cl2S2Si) calculated: 279.9379 found: 279.9362.
2,5-Dichloro-3-(4-methoxyphenyl)thieno[3,2-b]thiophene (4d)
Prepared according to TP1 from 2 (6.27 g, 30.0 mmol) and TMPMgCl· LiCl (27.4 mL, 1.15 M in
THF, 31.5 mmol). Deprotonation time: 45 min at 25 °C. A cross coupling reaction was
performed according to TP3 using 4-iodoanisole (7.72 g, 33.0 mmol), Pd(dba)2 (345 mg, 2%) and
tfp (279 mg, 4%) during 4 h at 25 °C. Flash column chromatographical purification on silica gel
(pentane/CH2Cl2 = 4:1) afforded 4d (6.70 g, 71%) as an off-white solid.
Mp. : 156.9-158.7 °C. 1H-NMR (C6D6, 400 MHz): δ = 7.44 (d, J = 8.92 Hz, 2H), 6.74 (d, J = 8.92 Hz, 2H), 6.30 (s,
1H), 3.25 (s, 3H). 13C-NMR (C6D6, 100 MHz): δ = 160.2, 136.3, 132.3, 131.5, 130.7, 129.8, 124.9, 124.7, 119.4,
114.6, 54.8.
IR (Diamond ATR, neat): ν~ = 3093 (w), 2838 (w), 1608 (m), 1532 (s), 1494 (s), 1288 (vs),
1247 (vs), 1175 (vs), 1029 (vs), 887 (m), 830 (vs), 814 (vs), 759 (s).
MS (EI, 70 eV): m/z = 314 (100) [M+], 299 (46), 271 (34), 202 (28), 85 (27), 57 (52).
HR-MS: (C13H8OCl2S2) calculated: 313.9394 found: 313.9375.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
61
2,5-Dichloro-3-(4-chlorophenyl)thieno[3,2-b]thiophene (4f)
Prepared according to TP1 from 2 (7.32 g, 35.0 mmol) and TMPMgCl· LiCl (33.5 mL, 1.15 M in
THF, 38.5 mmol). Deprotonation time: 45 min at 25 °C. A cross coupling reaction was
performed according to TP3 using 1-chloro-4-iodobenzene (9.18 g, 38.5 mmol) and Pd(dba)2
(604 mg, 3%) and tfp (488 mg, 6%) during 2 h at 25 °C. Flash column chromatographical
purification on silica gel (pentane) afforded 4f (10.23 g, 91%) as a pale yellow solid.
Mp. : 164.8-166.2 °C. 1H-NMR (C6D6, 400 MHz): δ = 7.15 (d, J = 8.81 Hz, 2H), 1.06 (d, J = 8.81 Hz, 2H), 6.24 (s,
1H). 13C-NMR (C6D6, 100 MHz): δ = 135.7, 134.7, 132.5, 130.9, 130.9, 130.4, 129.7, 129.2, 125.9,
119.3.
IR (Diamond ATR, neat): ν~ = 3090 (w), 1520 (m), 1486 (m), 1468 (s), 1094 (vs), 1035 (s), 886
(s), 832 (vs), 808 (vs), 767 (s).
MS (EI, 70 eV): m/z = 320 (100) [M+], 248 (36), 239 (9), 124 (9).
HR-MS: (C12H5Cl3S2) calculated: 319.8898 found: 319.8864.
Ethyl 2,5-dichlorothieno[3,2-b]thiophene-3-carboxylate (4h)
S
S
Cl
Cl
CO2Et
Prepared according to TP1 from 2 (6.27 g, 30.0 mmol) and TMPMgCl· LiCl (28.7 mL, 1.15 M in
THF, 33.0 mmol). Deprotonation time: 45 min at 25 °C. Ethyl cyanoformate (3.57 g, 36.0 mmol)
was added at -40 °C and the reaction mixture stirred for 1 h while warming to room temperature.
The reaction mixture was quenched with half concentrated aqueous NH4Cl solution, extracted
three times with Et2O, dried (MgSO4) and concentrated in vacuo. Flash column chromatographical
purification on silica gel (pentane/CH2Cl2 = 3:1) afforded 4h (7.73 g, 92%) as a white solid.
Mp. : 115.3-117.0 °C. 1H-NMR (C6D6, 400 MHz): δ = 6.17 (s, 1H), 3.99 (q, J = 7.13 Hz, 2H), 0.97 (t, J = 7.13 Hz,
3H). 13C-NMR (C6D6, 100 MHz): δ = 160.1, 137.6, 135.7, 133.1, 131.3, 122.7, 118.2, 61.3, 14.0.
IR (Diamond ATR, neat): ν~ = 3087 (m), 1715 (vs), 1500 (m), 1468 (s), 1224 (vs), 1174 (w),
1078 (s), 1021 (m), 1010 (m), 868 (m), 842 (m), 772 (m).
MS (EI, 70 eV): m/z = 280 (94) [M+], 252 (100), 235 (44), 207 (18), 103 (19).
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
62
HR-MS: (C9H6O2Cl2S2) calculated: 279.9186 found: 279.9172.
3-(Butylthio)-2,5-dichlorothieno[3,2-b]thiophene (4i)
Prepared according to TP1 from 2 (4.18 g, 20.0 mmol) and TMPMgCl· LiCl (19.1 mL, 1.15 Min
THF, 22.0 mmol). Deprotonation time: 45 min at 25 °C. PhSO2SBu (5.53 g, 24.0 mmol) was
added at 0°C and the reaction mixture stirred for 30 min at this temperature before warming to
room temperature. The reaction mixture was quenched with half concentrated aqueous NH4Cl
solution, extracted three times with Et2O, dried (MgSO4) and concentrated in vacuo. Flash column
chromatographical purification on silica gel (pentane) afforded 4i (5.58 g, 94%) as a pale yellow
oil. 1H-NMR (C6D6, 400 MHz): δ = 6.21 (s, 1H), 2.56 (t, J = 7.99 Hz, 2H), 1.30 (m, 2H), 1.17 (m,
2H), 0.67 (t, J = 7.30 Hz, 3H). 13C-NMR (C6D6, 100 MHz): δ = 139.5, 133.3, 131.7, 131.2, 122.9, 119.6, 34.2, 32.2, 21.7, 13.6.
IR (Diamond ATR, neat): ν~ = 3094 (w), 2918 (m), 1492 (m), 1440 (s), 1416 (s), 1336 (m),
1320 (m), 1309 (m), 1161 (m), 1155 (m), 1059 (s), 992 (m), 971 (m), 963 (m), 904 (vs), 854 (s), 833
(m), 793 (vs), 733 (w).
MS (EI, 70 eV): m/z = 296 (69) [M+], 240 (100), 205 (40), 57 (11).
HR-MS: (C10H10Cl2S3) calculated: 295.9322 found: 295.9317.
Ethyl 2,5-dichloro-6-(methylthio)thieno[3,2-b]thiophene-3-carboxylate (5a)
Prepared according to TP1 from 4a (4.90 g, 19.2 mmol) and TMPMgCl· LiCl (18.4 mL, 1.15 M in
THF, 21.1 mmol). Deprotonation time: 45 min at 25 °C. Ethyl cyanoformate (3.57 g, 24.0 mmol)
was added at -80 °C and the reaction mixture stirred for 3 h while warming to room temperature.
The reaction mixture was quenched with half concentrated aqueous NH4Cl solution, extracted
three times with Et2O, dried over Na2SO4 and concentrated in vacuo. Flash column
chromatographical purification on silica gel (pentane/CH2Cl2 = 2:1) afforded 5a (5.55 g, 89%) as
a yellow solid.
Mp. : 116.0-117.6 °C. 1H-NMR (C6D6, 300 MHz): δ = 4.01 (q, J = 7.13 Hz, 2H), 1.90 (s, 3H), 0.99 (t, J = 7.13 Hz,
3H).
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
63
13C-NMR (C6D6, 75 MHz): δ = 160.1, 137.8, 135.4, 134.7, 132.9, 123.1, 123.3, 61.4, 16.9, 14.1.
IR (Diamond ATR, neat): ν~ = 2018 (w), 1727 (vs), 1498 (s), 1224 (vs), 1081 (m), 1018 (s), 909
(m), 836 (m), 773 (m).
MS (EI, 70 eV): m/z = 326 (100) [M+], 300 (31), 285 (42), 255 (7), 127 (7).
HR-MS: (C10H8O2Cl2S3) calculated: 325.9063 found: 325.9069.
tert-Butyl 2,5-dichloro-6-(phenylthio)thieno[3,2-b]thiophene-3-carboxylate (5b)
Prepared according to TP1 from 4b (952 mg, 3.0 mmol) and TMPMgCl· LiCl (2.87 mL, 1.15 M
in THF, 3.3 mmol). Deprotonation time: 45 min at 25 °C. Boc2O (786 mg, 3.6 mmol) was added
at -40 °C and the reaction mixture stirred for 12 h while warming to room temperature. The
reaction mixture was quenched with half concentrated aqueous NH4Cl solution, extracted three
times with Et2O, dried over Na2SO4 and concentrated in vacuo. Flash column chromatographical
purification on silica gel (pentane/CH2Cl2 = 4:1) afforded 5b (879 mg, 70%) as a yellow solid.
Mp. : 123.3-124.2 °C. 1H-NMR (CDCl3, 300 MHz): δ = 7.29 (m, 5H), 1.66 (s, 9H). 13C-NMR (CDCl3, 75 MHz): δ = 159.5, 138.2, 134.9, 134.3, 132.8, 132.8, 130.0, 129.4, 127.6,
123.5, 120.8, 83.5, 28.3.
IR (Diamond ATR, neat): ν~ = 1698 (vs), 1580 (w), 1477 (m), 1444 (m), 1154 (w), 1059 (m),
1024 (w), 909 (m), 853 (w), 806 (s), 734 (vs), 686 (s).
MS (EI, 70 eV): m/z = 416 (26)[M+], 360 (100), 325 (24), 307 (29), 290 (31), 246 (33).
HR-MS: (C17H14O2Cl2S3) calculated: 415.9533 found: 415.9522.
(2,5-Dichloro-6-(trimethylsilyl)thieno[3,2-b]thiophen-3-yl)(phenyl)methanone (5c)
Prepared according to TP1 from 4c (1.20 g, 4.3 mmol) and TMPMgCl· LiCl (4.1 mL, 1.15 M in
THF, 4.7 mmol). Deprotonation time: 45 min at 25 °C. An acylation reaction was perfomed
according to TP4 using benzoyl chloride (770 mg, 5.5 mmol) at -40 °C during 3 h. Flash column
chromatographical purification on silica gel (pentane/CH2Cl2 = 3:1) afforded 5c (1.55 g, 95%) as
a yellow solid.
Mp. : 100.4-101.5 °C. 1H-NMR (C6D6, 400 MHz): δ = 7.64 (m, 2H), 7.12 (m, 1H), 7.03 (m, 2H), 0.30 (s, 9H).
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
64
13C-NMR (C6D6, 100 MHz): δ = 188.3, 139.3, 137.8, 137.7, 136.4, 134.3, 132.8, 130.3, 129.5,
129.2, 128.6, -0.7.
IR (Diamond ATR, neat): ν~ = 1642 (s), 1598 (w), 1438 (m), 1344 (s), 1244 (vs), 1050 (s), 861
(vs), 837 (vs), 733 (s), 690 (vs).
MS (EI, 70 eV): m/z = 384 (89) [M+], 369 (47), 105 (100), 77 (41).
HR-MS: (C16H14OCl2S2Si) calculated: 383.9632 found: 383.9632.
tert-Butyl 2,5-dichloro-6-(4-methoxyphenyl)thieno[3,2-b]thiophene-3-carboxylate (5d)
Prepared according to TP1 from 4d (6.30 g, 20.0 mmol) and TMPMgCl· LiCl (18.3 mL, 1.15 M in
THF, 21.0 mmol). Deprotonation time: 1 h at 25 °C. Boc2O (6.55 g, 30.0 mmol) was added at
-40 °C and the reaction mixture stirred for 12 h while warming to room temperature. The
reaction mixture was quenched with half concentrated aqueous NH4Cl solution, extracted three
times with Et2O, dried (MgSO4) and concentrated in vacuo. Flash column chromatographical
purification on silica gel (pentane/CH2Cl2 = 4:1) afforded 5d (6.13 g, 73%) as a pale yellow solid.
Mp. : 132.2-134.1 °C. 1H-NMR (C6D6, 400 MHz): δ = = 7.43 (d, J = 7.99 Hz, 2H), 6.78 (d, J = 7.99 Hz, 2H), 3.28 (s,
3H), 1.45 (s, 9H). 13C-NMR (C6D6, 100 MHz): δ = 160.2, 159.5, 136.9, 133.5, 132.6, 130.9, 129.8, 126.6, 124.7,
124.3, 114.7, 82.6, 54.8, 28.1.
IR (Diamond ATR, neat): ν~ = 2934 (w), 2358 (w), 1693 (vs), 1611 (m), 1528 (s), 1497 (s),
1352 (m), 1254 (vs), 1159 (s), 1031 (vs), 823 (vs), 737 (vs), 710 (m).
MS (EI, 70 eV): m/z = 414 (21) [M+], 358 (100), 343 (32), 278 (26), 207 (49).
HR-MS: (C18H16O3Cl2S2) calculated: 414.9997 [M+H] found: 414.9983.
1-(2,5-Dichloro-6-(4-methoxyphenyl)thieno[3,2-b]thiophen-3-yl)-2,2-dimethylpropan-1-
one (5e)
Prepared according to TP1 from 4d (3.15 g, 10.0 mmol) and TMPMgCl· LiCl (9.6 mL, 1.15 M in
THF, 11.0 mmol). Deprotonation time: 1 h at 25 °C. An acylation reaction was perfomed
according to TP4 using pivaloyl chloride (1.45 g, 12.0 mmol) at -20 °C during 3 h while warming
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
65
to room temperature. Flash column chromatographical purification on silica gel (pentane/CH2Cl2
= 4:1) afforded 5e (3.37 g, 85%) as a white solid.
Mp. : 14.1-115.6 °C. 1H-NMR (CDCl3, 300 MHz): δ = 7.56 (d, J = 9.00 Hz, 2H), 7.02 (d, J = 9.00 Hz, 2H), 3.87 (s,
3H), 1.38 (s, 9H). 13C-NMR (CDCl3, 75 MHz): δ = 205.1, 159.8, 134.4, 132.3, 131.7, 130.5, 129.6, 128.0, 126.0,
124.5, 114.5, 55.4, 45.3, 26.8.
IR (Diamond ATR, neat): ν~ = 2954 (w), 1740 (w), 1736 (w), 1642 (s), 1609 (m), 1575 (w),
1534 (m), 1492 (m), 1464 (w), 1451 (s), 1406 (w), 1392 (w), 1365 (w), 1349 (w), 1339 (w), 1326
(m), 1307 (w), 1291 (m), 1245 (vs), 1218 (w), 1204 (w), 1177 (s), 1131 (s), 1113 (m), 1042 (m),
1034 (m), 1026 (m), 1009 (w), 979 (m), 961 (w), 897 (m), 874 (m), 837 (vs), 816 (m), 813 (w), 798
(w), 787 (s), 770 (w), 760 (m), 740 (w).
MS (EI, 70 eV): m/z = 398 (54) [M+], 341 (100), 278 (41), 127 (8), 57 (25).
HR-MS: (C18H16O2Cl2S2) calculated: 397.9969 found: 397.9962.
1-(2,5-Dichloro-6-(4-chlorophenyl)thieno[3,2-b]thiophen-3-yl)-2,2-dimethylpropan-1-one
(5f)
Prepared according to TP1 from 4f (9.90 g, 30.0 mmol) and TMPMgCl· LiCl (29.6 mL, 1.15 M in
THF, 34.0 mmol). Deprotonation time: 45 min at 25 °C. An acylation reaction was perfomed
according to TP4 using pivaloyl chloride (4.11 g, 34.0 mmol) at -20 °C during 3 h. Flash column
chromatographical purification on silica gel (pentane/CH2Cl2 = 4:1) afforded 5f (10.85 g, 86%) as
a white solid.
Mp. : 135.1-137.6 °C. 1H-NMR (C6D6, 400 MHz): δ = 7.14 (m, 2H), 7.08 (m, 2H), 1.21 (s, 9H). 13C-NMR (C6D6, 100 MHz): δ = 203.1, 134.8, 133.9, 133.0, 132.7, 130.6, 129.8, 129.8, 129.4,
128.4, 127.6, 44.9, 26.5.
IR (Diamond ATR, neat): ν~ = 2970 (w), 2927 (w), 1641 (s), 1597 (w), 1526 (w), 1482 (s), 1464
(w), 1450 (s), 1421 (w), 1394 (m), 1365 (w), 1356 (w), 1345 (m), 1336 (m), 1324 (m), 1301 (w),
1130 (s), 1107 (m), 1093 (s), 1037 (w), 1015 (m), 976 (m), 963 (w), 892 (m), 869 (m), 835 (vs), 797
(w), 771 (m), 766 (m), 720 (m), 706 (w).
MS (EI, 70 eV): m/z = 402 (23) [M+], 347 (100), 282 (34), 57 (30).
HR-MS: (C17H13OCl3S2) calculated: 401.9473 found: 401.9471.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
66
Ethyl 2,5-dichloro-6-(4-chlorophenyl)thieno[3,2-b]thiophene-3-carboxylate (5g)
Prepared according to TP1 from 4f (1.28 g, 5.0 mmol) and TMPMgCl· LiCl (4.78 mL, 1.15 M in
THF, 5.5 mmol). Deprotonation time: 1 h at 25 °C. Ethyl cyanoformate (595 mg, 6.0 mmol) was
added at -40 °C and the reaction mixture stirred for 1 h while warming to room temperature. The
reaction mixture was quenched with half concentrated aqueous NH4Cl solution, extracted three
times with Et2O, dried (MgSO4) and concentrated in vacuo. Flash column chromatographical
purification on silica gel (pentane/CH2Cl2 = 3:1) afforded 5g (1.59 g, 81%) as a white solid.
Mp. : 150.4-152.6 °C. 1H-NMR (C6D6, 400 MHz): δ = 7.14 (m, 2H), 7.10 (m, 2H), 4.04 (q, J = 7.13 Hz, 2H), 1.01 (t, J
= 7.13 Hz, 3H). 13C-NMR (C6D6, 100 MHz): δ = 160.2, 137.5, 134.8, 133.7, 132.3, 130.6, 129.8, 129.4, 128.1,
127.9, 123.1, 61.5, 14.1.
IR (Diamond ATR, neat): ν~ = 2983 (w), 2904 (vw), 1727 (s), 1684 (w), 1499 (s), 1481 (w),
1476 (m), 1439 (vw), 1391 (w), 1361 (vw), 1350 (w), 1341 (w), 1225 (vs), 1192 (m), 1156 (w), 1112
(w), 1091 (m), 1080 (m), 1032 (m), 1012 (m), 958 (vw), 948 (w), 895 (m), 879 (w), 838 (m), 828
(m), 781 (w), 771 (m), 740 (w), 721 (w), 706 (vw).
MS (EI, 70 eV): m/z = 392 (100) [M+], 367 (35), 362 (86), 345 (18), 282 (39), 248 (21).
HR-MS: (C15H9O2Cl3S2) calculated: 389.9110 found: 389.9106.
Diethyl 2,5-dichlorothieno[3,2-b]thiophene-3,6-dicarboxylate (5h)
Prepared according to TP1 from 4h (10.87 g, 34.0 mmol) and TMPMgCl· LiCl (32.5 mL, 1.15 M
in THF, 37.4 mmol). Deprotonation time: 20 min at -20 °C. Ethyl cyanoformate (3.21 g, 32.4
mmol) was added at -20 °C and the reaction mixture stirred for 12 h while warming to room
temperature. The reaction mixture was quenched with half concentrated aqueous NH4Cl
solution, extracted three times with Et2O, dried (MgSO4) and concentrated in vacuo. Flash column
chromatographical purification on silica gel (pentane/CH2Cl2 = 3:1) afforded 5h (10.79 g, 81%)
as a white solid.
Mp. : 141.6-142.9 °C.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
67
1H-NMR (C6D6, 400 MHz): δ = 7.14 (m, 2H), 7.19 (m, 2H), 4.04 (q, J = 7.14 Hz, 2H), 1.01 (t, J
= 7.14 Hz, 3H). 13C-NMR (C6D6, 100 MHz): δ = 160.2, 137.5, 134.8, 133.7, 132.3, 130.6, 129.8, 129.4, 128.1,
127.9, 123.1, 61.5, 14.1.
IR (Diamond ATR, neat): ν~ = 3111 (w), 2992 (w), 1703 (vs), 1684 (m), 1501 (s), 1470 (m),
1456 (w), 1389 (w), 1371 (w), 1360 (w), 1221 (vs), 1165 (m), 1141 (m), 1115 (m), 1019 (s), 1001
(m), 875 (s), 849 (m), 831 (m), 821 (m), 721 (vs), 696 (m).
MS (EI, 70 eV): m/z = 392 (100) [M+], 364 (96), 345 (18), 282 (39), 203 (15).
HR-MS: (C12H10O4Cl2S2) calculated: 351.9390 found: 351.9398.
Ethyl 6-(butylthio)-2,5-dichlorothieno[3,2-b]thiophene-3-carboxylate (5i)
Prepared according to TP1 from 4i (5.35 g, 18.0 mmol) and TMPMgCl· LiCl (17.47 mL, 1.15 M
in THF, 20.0 mmol). Deprotonation time: 1 h at 25 °C. Ethyl cyanoformate (2.1 g, 22.0 mmol)
was added at -40 °C and the reaction mixture stirred for 2 h while warming to room temperature.
The reaction mixture was quenched with half concentrated aqueous NH4Cl solution, extracted
three times with Et2O, dried (MgSO4) and concentrated in vacuo. Flash column chromatographical
purification on silica gel (pentane/CH2Cl2 = 2:1) afforded 5i (5.50 g, 83%) as a green oil. 1H-NMR (C6D6, 400 MHz): δ = 3.99 (q, J = 7.13 Hz, 2H), 2.55 (7, J = 7.99 Hz, 2H), 1.32 (m,
2H), 1.19 (m, 2H), 0.97 (t, J = 7.13 Hz, 3H), 0.70 (t, J = 7.88 Hz, 3H). 13C-NMR (C6D6, 100 MHz): δ = 160.0, 137.8, 136.4, 135.9, 132.8, 123.4, 122.2, 61.4, 34.4, 32.2,
21.7, 14.0, 13.6.
IR (Diamond ATR, neat): ν~ = 2957 (w), 2928 (w), 2871 (w), 1730 (s), 1698 (s), 1495 (s), 1463
(w), 1446 (m), 1392 (w), 1374 (m), 1351 (m), 1301 (w), 1245 (s), 1216 (vs), 1171 (w), 1156 (w),
1144 (w), 1094 (w), 1074 (s), 1057 (m), 1018 (m), 947 (w), 905 (s), 870 (w), 836 (m), 774 (m), 756
(w), 742 (w), 730 (w).
MS (EI, 70 eV): m/z = 280 (94) [M+], 252 (100), 235 (44), 207 (18), 103 (19).
HR-MS: (C13H14O2Cl2S3) calculated: 367.9533 found: 367.9529.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
68
Preparation of 3,6-Disubstituted Thieno[3,2-b]thiophenes
Ethyl 6-(methylthio)thieno[3,2-b]thiophene-3-carboxylate (6a)
Prepared according to TP5 from 5a (4.91 g, 15.0 mmol) in 30 mL EtOH, HCO2NH4 (2.84 g,
45.0 mmol), and Pd/C (320 mg, 1 mol %). Total reaction time: 6 h. Flash column chroma-
tographical purification on silica gel (pentane/CH2Cl2 = 4:1) afforded 6a (2.89 g, 77%) as a pale
yellow solid.
Mp. : 72.2-74.1 °C. 1H-NMR (C6D6, 400 MHz): δ = 7.72 (d, J = 1.57 Hz, 1H), 6.65 (d, J = 1.57 Hz, 1H), 4.07 (q, J
= 7.12 Hz, 2H), 1.98 (s, 3H), 1.02 (t, J = 7.12 Hz, 3H). 13C-NMR (C6D6, 100 MHz): δ = 161.5, 140.2, 139.0, 134.5, 127.2, 126.2, 125.5, 61.0, 16.9, 14.2.
IR (Diamond ATR, neat): ν~ = 3099 (w), 2975 (w), 1698 (s), 1500 (m), 1468 (w), 1455 (w),
1447 (w), 1434 (w), 1390 (w), 1334 (w), 1315 (w), 1239 (vs), 1167 (w), 1142 (w), 1045 (m), 1008
(m), 974 (m), 961 (m), 879 (m), 850 (w), 832 (m), 767 (w), 725 (vs), 705 (m).
MS (EI, 70 eV): m/z = 258 (100) [M+], 230 (36), 215 (27), 197 (21), 69 (11).
HR-MS: (C10H10O2S3) calculated: 257.9843 found: 257.9840.
Diethyl thieno[3,2-b]thiophene-3,6-dicarboxylate (6b)
Prepared according to TP5 from 5h (5.51 g, 15.6 mmol) in 30 mL EtOH, HCO2NH4 (2.95 g,
46.8 mmol), and Pd/C (664 mg, 2 mol %). Total reaction time: 4 h. Flash column chroma-
tographical purification on silica gel (pentane/CH2Cl2 = 2:1) afforded 6b (3.61 g, 81%) as a pale
yellow solid.
Mp. : 119.5-121.5 °C. 1H-NMR (C6D6, 300 MHz): δ = 7.77 (s, 2H), 4.06 (q, J = 7.13 Hz, 4H), 1.01 (t, J = 7.13 Hz,
6H). 13C-NMR (C6D6, 75 MHz): δ = 161.5, 140.2, 139.0, 134.5, 127.2, 126.2, 125.5, 61.0, 16.9, 14.2.
IR (Diamond ATR, neat): ν~ = 3107 (w), 2989 (w), 1711 (vs), 1678 (m), 1499 (s), 1472 (m),
1452 (w), 1388 (w), 1377 (w), 1355 (w), 1230 (vs), 1159 (m), 1141 (m), 1117 (m), 1026 (s), 1003
(m), 876 (s), 849 (m), 831 (m), 821 (m), 725 (vs), 696 (m).
MS (EI, 70 eV): m/z = 284 (100) [M+], 256 (20), 239 (78), 211 (74), 183 (27), 69 (19).
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
69
HR-MS: (C12H12O4S2) calculated: 284.0177 found: 284.0176.
Phenyl(6-(trimethylsilyl)thieno[3,2-b]thiophen-3-yl)methanone (6c)
Prepared according to TP5 from 5c (270 mg, 0.7 mmol) in 5 mL EtOH, HCO2NH4 (190 mg, 3.0
mmol), and Pd/C (44 mg, 2 mol %). Total reaction time: 4 h. Flash column chromatographical
purification on silica gel (pentane/CH2Cl2 = 2:1) afforded 6c (159 mg, 71%) as a pale yellow
solid.
Mp. : 92.8-94.4 °C. 1H-NMR (C6D6, 300 MHz): δ = 7.67 (m, 2H), 7.33 (d, J = 1.61 Hz, 1H), 7.15 (d, J = 1.61 Hz,
1H), 7.12 (m, 1H), 7.06 (m, 2H), 0.27 (s, 9H). 13C-NMR (C6D6, 75 MHz): δ = 187.8, 143.6, 140.7, 139.0, 137.6, 136.5, 133.7, 131.9, 131.7,
129.3, 128.5, -1.1.
IR (Diamond ATR, neat): ν~ = 2942 (vw), 1642 (m), 1598 (w), 1578 (vw), 1490 (w), 1477 (m),
1438 (m), 1410 (w), 1344 (m), 1315 (w), 1298 (w), 1277 (w), 1244 (s), 1177 (w), 1159 (vw), 1106
(w), 1077 (vw), 1050 (m), 1027 (w), 1000 (vw), 977 (w), 896 (w), 861 (s), 836 (vs), 813 (s), 782 (w),
761 (m), 733 (s), 720 (m), 690 (s), 668 (m).
MS (EI, 70 eV): m/z = 316 (38) [M+], 301 (100), 105 (18), 77 (21).
HR-MS: (C16H16OS2Si) calculated: 316.0412 found: 316.0410.
Ethyl 6-(butylthio)thieno[3,2-b]thiophene-3-carboxylate (6d)
S
S
SBu
EtO2C
Prepared according to TP5 from 5i (5.17 g, 14.0 mmol) in 30 mL EtOH, HCO2NH4 (2.65 g,
42.0 mmol), and Pd/C (596 mg, 2 mol %). Total reaction time: 6 h. Flash column chroma-
tographical purification on silica gel (pentane/CH2Cl2 = 3:1) afforded 6d (3.06 g, 72%) as a
yellow viscous oil. 1H-NMR (C6D6, 400 MHz): δ = 7.73 (d, J = 1.57 Hz, 1H), = 6.88 (d, J = 1.57 Hz, 1H), 4.06 (q,
J = 7.13 Hz, 2H), 2.60 (t, J = 7.99 Hz, 2H), 1.38 (m, 2H), 1.20 (m, 2H), 1.01 (t, J = 7.13 Hz, 3H),
0.70 (t, J = 7.33 Hz, 3H). 13C-NMR (C6D6, 100 MHz): δ = 161.5, 141.8, 138.8, 134.5, 129.2, 127.3, 124.5, 60.9, 34.5, 31.8,
21.8, 14.2, 13.6.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
70
IR (Diamond ATR, neat): ν~ = 3099 (vw), 2956 (w), 2927 (w), 2869 (w), 1705 (s), 1497 (m),
1464 (w), 1390 (w), 1375 (m), 1357 (w), 1332 (w), 1319 (w), 1300 (w), 1228 (vs), 1171 (w), 1143
(m), 1113 (w), 1094 (w), 1044 (s), 1007 (w), 973 (m), 914 (w), 877 (w), 856 (w), 828 (m), 777 (w),
733 (s), 707 (m), 668 (m).
MS (EI, 70 eV): m/z = 300 (83) [M+], 244 (100), 240 (23), 216 (24), 198 (20).
HR-MS: (C13H16O2S3) calculated: 300.0312 found: 300.0306.
Ethyl 6-(4-chlorophenyl)thieno[3,2-b]thiophene-3-carboxylate (6e)
Prepared according to TP5 from 5g (783 mg, 2.0 mmol) in 8 mL EtOH, HCO2NH4 (380 mg,
6.0 mmol), and Pd/C (85 mg, 2 mol %). Total reaction time: 5 h. Flash column chroma-
tographical purification on silica gel (pentane/CH2Cl2 = 3:1) afforded 6e (507 mg, 78%) as a
white solid.
Mp. : 125.8-126.9 °C. 1H-NMR (CDCl3, 300 MHz): δ = 7.78 (d, J = 1.60 Hz, 1H), 7.23(m, 2H), 7.12 (m, 2H), 6.90 (d,
J = 1.60 Hz, 1H), 4.11 (q, J = 7.12 Hz, 2H), 1.05 (t, J = 7.12 Hz, 3H). 13C-NMR (CDCl3, 75 MHz): δ = 161.6, 139.8, 137.5, 134.1, 133.7, 133.2, 129.3, 127.9, 127.0,
126.7, 125.3, 61.0, 14.3.
IR (Diamond ATR, neat): ν~ = 2983 (w), 2904 (vw), 1727 (s), 1684 (w), 1499 (s), 1481 (w),
1476 (m), 1439 (vw), 1391 (w), 1361 (vw), 1350 (w), 1341 (w), 1297 (vw), 1225 (vs), 1192 (m),
1156 (w), 1112 (w), 1091 (m), 1080 (m), 1032 (m), 1012 (m), 958 (vw), 948 (w), 895 (m), 879 (w),
838 (m), 828 (m), 781 (w), 771 (m), 740 (w), 721 (w), 706 (vw).
MS (EI, 70 eV): m/z = 322 (100) [M+], 294 (65); 277 (27), 214 (39), 139 (12).
HR-MS: (C15H11O2ClS2) calculated: 321.9889 found: 321.9888.
tert-Butyl 6-(4-methoxyphenyl)thieno[3,2-b]thiophene-3-carboxylate (6f)
Prepared according to TP5 from 5d (2.64 g, 6.4 mmol) in 15 mL EtOH, HCO2NH4 (1.21 g, 19.2
mmol), and Pd/C (320 mg, 2 mol %). Total reaction time: 6 h. Flash column chromatographical
purification on silica gel (pentane/CH2Cl2 = 2:1) afforded 6f (3.78 g, 85%) as a yellow solid.
Mp. : 120.0-121.8°C.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
71
1H-NMR (C6D6, 400 MHz): δ = 7.80 (d, J = 1.62 Hz, 1H), 7.52 (d, J = 7.99 Hz, 2H), 7.02 (d, J
= 1.62 Hz, 1H), 6.80 (d, J = 7.99 Hz, 2H), 3.31 (s, 3H), 1.50 (s, 9H). 13C-NMR (C6D6, 100 MHz): δ = 161.1, 159.7, 139.6, 137.8, 134.3, 133.7, 128.6, 127.6, 123.4,
114.7, 81.4, 54.8, 28.2.
IR (Diamond ATR, neat): ν~ = 2934 (w), 2358 (w), 2339 (w), 2333 (w), 1693 (s), 1611 (m),
1528 (s), 1511 (w), 1497 (s), 1480 (w), 1466 (w), 1450 (m), 1440 (m), 1391 (w), 1361 (m), 1352
(m), 1336 (w), 1308 (w), 1281 (w), 1267 (s), 1254 (vs), 1225 (m), 1201 (w), 1184 (s), 1159 (s), 1116
(m), 1045 (m), 1031 (s), 972 (w), 962 (w), 949 (m), 845 (m), 823 (s), 792 (m), 768 (w), 737 (vs),
721 (w), 710 (m), 702 (w), 669 (w).
MS (EI, 70 eV): m/z = 346 (28) [M+], 290 (100), 275 (30), 247 (10).
HR-MS: (C18H18O3S2) calculated: 346.0697 found: 346.0693.
1-(6-(4-Methoxyphenyl)thieno[3,2-b]thiophen-3-yl)-2,2-dimethylpropan-1-one (6g)
Prepared according to TP5 from 5e (3.20 g, 8.0 mmol) in 15 mL EtOH, HCO2NH4 (1.52 g, 24.0
mmol), and Pd/C (340 mg, 2 mol %). Total reaction time: 5 h. Flash column chromatographical
purification on silica gel (pentane/CH2Cl2 = 2:1) afforded 6g (2.11 g, 80%) as a white solid.
Mp. : 136.8-138.6 °C. 1H-NMR (CDCl3, 300 MHz): δ = 8.23 (s, 1H), 7.67 (d, J = 9.00 Hz, 2H), 7.53 (s, 1H), 7.02 (d, J
= 9.00 Hz, 2H), 3.88 (s, 3H), 1.47 (s, 9H). 13C-NMR (CDCl3, 75 MHz): δ = 199.4, 159.2, 141.1, 135.4, 133.3, 132.5, 131.4, 127.7, 127.3,
124.3, 114.5, 55.4, 44.0, 28.5.
IR (Diamond ATR, neat): ν~ = 3106 (w), 3095 (w), 2973 (w), 2929 (w), 1651 (s), 1610 (m),
1576 (w), 1524 (m), 1486 (m), 1475 (m), 1467 (m), 1443 (w), 1433 (w), 1393 (w), 1369 (w), 1351
(w), 1339 (w), 1306 (w), 1283 (m), 1249 (s), 1217 (m), 1182 (m), 1167 (m), 1149 (m), 1143 (m),
1123 (m), 1031 (s), 949 (m), 914 (s), 847 (m), 829 (s), 824 (s), 813 (m), 805 (w), 789 (m), 772 (w),
762 (w), 746 (vs), 711 (m).
MS (EI, 70 eV): m/z = 330 (51) [M+], 273 (100), 232 (8), 202 (6), 57 (6).
HR-MS: (C18H18O2S2) calculated: 330.0748 found: 330.0739.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
72
Preparation of Fully Functionalized Thieno[3,2-b]thiophenes
Ethyl 2-(4-methoxyphenyl)-6-(methylthio)thieno[3,2-b]thiophene-3-carboxylate (7a)
Prepared according to TP1 from 6a (775 mg, 3.0 mmol) and TMPMgCl· LiCl (2.87 mL, 1.15 M
in THF, 3.3 mmol). Deprotonation time: 40 min at -20 °C. A cross coupling reaction was
performed according to TP3 using 4-iodoanisole (772 mg, 3.3 mmol) and Pd(dba)2 (52 mg, 3%)
and tfp (42 mg, 6%) during 2 h at 25 °C. Flash column chromatographical purification on silica
gel (pentane/CH2Cl2 = 2:1) afforded 7a (1.00 g, 91%) as a pale yellow solid.
Mp. : 83.8-85.0 °C. 1H-NMR (C6D6, 400 MHz): δ = 7.42 (d, J = 8.00 Hz, 2H), 6.71 (d, J = 8.00 Hz, 2H), 6.71(s,
1H), 4.11 (q, J = 7.12 Hz, 2H), 3.25 (s, 3H), 2.03 (s, 3H), 0.91 (t, J = 7.12 Hz, 3H). 13C-NMR (C6D6, 100 MHz): δ = 161.9, 160.7, 153.7, 141.2, 137.0, 131.9, 126.5, 125.9, 124.6,
121.6, 113.6, 60.7, 54.8, 17.0, 14.0.
IR (Diamond ATR, neat): ν~ = 2996 (w), 2979 (w), 2936 (w), 2922 (w), 2834 (w), 1720 (vs),
1608 (m), 1573 (w), 1524 (m), 1488 (s), 1470 (w), 1460 (m), 1449 (m), 1433 (w), 1426 (w), 1415
(w), 1390 (w), 1364 (w), 1294 (m), 1274 (s), 1246 (vs), 1199 (vs), 1175 (vs), 1154 (m), 1118 (m),
1047 (m), 1031 (s), 1023 (s), 1009 (m), 977 (m), 961 (w), 954 (w), 943 (w), 923 (w), 842 (m), 819
(vs), 798 (m), 793 (m), 779 (m), 740 (m), 702 (s).
MS (EI, 70 eV): m/z = 364 (100) [M+], 349 (10), 336 (26), 321 (21), 303 (14).
HR-MS: (C17H16O3S3) calculated: 365.0340 [M+H] found: 365.0329.
Ethyl 6-(methylthio)-2-(4-(trifluoromethyl)phenyl)thieno[3,2-b]thiophene-3-carboxylate
(7b)
Prepared according to TP1 from 6a (646 mg, 2.0 mmol) and TMPMgCl· LiCl (1.91 mL, 1.15 M in
THF, 2.2 mmol). Deprotonation time: 40 min at -20 °C. A cross coupling reaction was
performed according to TP3 using 4-iodobenzotrifluoride (653 mg, 2.4 mmol) and Pd(dba)2 (34
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
73
mg, 3%) and tfp (28 mg, 6%) during 3 h at 25 °C. Flash column chromatographical purification
on silica gel (pentane/CH2Cl2 = 2:1) afforded 7b (740 mg, 92%) as a pale yellow oil. 1H-NMR (C6D6, 300 MHz): δ = 7.30 (d, J = 7.98 Hz, 2H), 7.24 (d, J = 7.98 Hz, 2H), 6.69 (s,
1H), 3.92 (q, J = 7.12 Hz, 2H), 2.03 (s, 3H), 0.82 (t, J = 7.12 Hz, 3H). 13C-NMR (C6D6, 75 MHz): δ = 161.4, 150.6, 141.1, 138.0, 137.5 (q, J = 0.8 Hz), 130.5, 130.8,
128.0 (q, J = 24.9 Hz), 126.1, 125.3, 124.9 (q, J = 3.8 Hz), 124.8 (q, J = 272 Hz), 61.0, 16.9, 13.8.
IR (Diamond ATR, neat): ν~ = 2983 (w), 2964 (w), 1616 (m), 1493 (w), 1476 (w), 1465 (w),
1438 (m), 1405 (m), 1388 (w), 1370 (w), 1318 (s), 1275 (s), 1207 (m), 1188 (m), 1162 (vs), 1134
(vs), 1110 (s), 1067 (m), 1044 (s), 1014 (m), 990 (s), 954 (w), 947 (w), 921 (m), 872 (w), 852 (w),
842 (w), 833 (m), 794 (w), 780 (m), 760 (w), 756 (w), 736 (w), 697 (w).
MS (EI, 70 eV): m/z = 402 (100) [M+], 374 (30), 341 (24), 57 (14), 44 (37).
HR-MS: (C17H13O2F3S3) calculated: 402.0030 found: 402.0021.
Ethyl 6-(methylthio)-2-pivaloylthieno[3,2-b]thiophene-3-carboxylate (7c)
Prepared according to TP1 from 6a (646 mg, 2.0 mmol) and TMPMgCl· LiCl (1.91 mL, 1.15 M in
THF, 2.2 mmol). Deprotonation time: 40 min at -20 °C. An acylation reaction was perfomed
according to TP4 using pivaloyl chloride (362 mg, 3.0 mmol) at -20 °C during 2 h. Flash column
chromatographical purification on silica gel (pentane/CH2Cl2 = 2:1) afforded 7c (682 mg, 94%)
as a pale yellow oil. 1H-NMR (C6D6, 400 MHz): δ = 6.60 (s, 1H), 3.97 (q, J = 7.12 Hz, 2H), 1.94 (s, 3H), 1.20 (s,
9H), 0.94 (t, J = 7.12 Hz, 3H). 13C-NMR (C6D6, 100 MHz): δ = 204.1, 161.2, 147.6, 138.9, 138.3, 126.2, 126.0, 124.3, 61.5, 45.0,
26.7, 17.0, 14.0.
IR (Diamond ATR, neat): ν~ = 2918 (w), 2903 (w), 1717 (vs), 1686 (s), 1650 (w), 1601 (w),
1515 (m), 1507 (s), 1472 (m), 1459 (m), 1440 (m), 1406 (w), 1389 (w), 1373 (w), 1363 (w), 1357
(w), 1262 (s), 1247 (s), 1239 (s), 1226 (vs), 1195 (m), 1149 (s), 1113 (m), 1106 (w), 1038 (m), 1028
(m), 990 (m), 976 (m), 960 (w), 927 (m), 895 (m), 872 (w), 842 (m), 829 (s), 815 (m), 780 (w), 760
(w), 749 (m), 678 (w), 672 (w).
MS (EI, 70 eV): m/z = 342 (17) [M+], 285 (47), 257 (100), 140 (6).
HR-MS: (C15H18O3S3) calculated: 342.0418 found: 342.0421.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
74
Ethyl 6-(methylthio)-2-(phenylthio)thieno[3,2-b]thiophene-3-carboxylate (7d)
Prepared according to TP1 from 6a (775 mg, 3.0 mmol) and TMPMgCl· LiCl (2.87 mL, 1.15 M in
THF, 3.3 mmol). Deprotonation time: 40 min at -20 °C. PhSO2SPh (901 mg, 3.6 mmol) was
added at 0 °C and the reaction mixture stirred for 3 h. The reaction mixture was quenched with
half concentrated aqueous NH4Cl solution, extracted three times with Et2O, dried (MgSO4) and
concentrated in vacuo. Flash column chromatographical purification on silica gel (pentane/CH2Cl2
= 2:1) afforded 7c (0.99 g, 91%) as a yellow solid.
Mp. : 66.6-68.6 °C. 1H-NMR (C6D6, 300 MHz): δ = 7.46 (m, 2H), 6.94 (m, 3H), 6.55 (s, 1H), 4.15 (q, J = 7.12 Hz,
2H), 1.82 (s, 3H), 1.08 (t, J = 7.12 Hz, 3H). 13C-NMR (C6D6, 75 MHz): δ = 161.8, 154.0, 139.9, 136.3, 135.0, 132.7, 130.0, 129.9, 126.1,
123.5, 121.3, 61.1, 17.0, 14.3.
IR (Diamond ATR, neat): ν~ = 2978 (w), 2971 (w), 2924 (w), 2900 (w), 1698 (s), 1659 (w),
1581 (w), 1573 (w), 1485 (m), 1472 (m), 1449 (m), 1438 (m), 1422 (m), 1390 (w), 1374 (w), 1363
(w), 1345 (w), 1329 (m), 1312 (w), 1303 (w), 1228 (vs), 1175 (m), 1161 (w), 1155 (w), 1113 (w),
1091 (w), 1075 (s), 1024 (s), 999 (w), 988 (w), 978 (m), 970 (w), 952 (w), 944 (m), 917 (w), 876
(w), 843 (m), 824 (w), 773 (m), 753 (s), 726 (m), 719 (w), 697 (s), 689 (s).
MS (EI, 70 eV): m/z = 366 (100) [M+], 338 (18), 305 (16), 274 (15), 246 (27).
HR-MS: (C16H14O2S4) calculated: 366.9956 [M+H] found: 366.9944.
1-(6-(4-Methoxyphenyl)-2-(methylthio)thieno[3,2-b]thiophen-3-yl)-2,2-dimethylpropan-1-
one (7e)
Prepared according to TP1 from 6g (826 mg, 2.5 mmol) and TMPMgCl· LiCl (2.39 mL, 1.15 M
in THF, 2.75 mmol). Deprotonation time: 20 min at -50 °C. PhSO2SMe (678 mg, 3.6 mmol) was
added at -50 °C and the reaction mixture stirred for 1 h while warming to room temperature. The
reaction mixture was quenched with half concentrated aqueous NH4Cl solution, extracted three
times with Et2O, dried (MgSO4) and concentrated in vacuo. Flash column chromatographical
purification on silica gel (pentane/CH2Cl2 = 2:1) afforded 7e (880 mg, 94%) as a white solid.
Mp. : 125.8 - 127.6 °C.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
75
1H-NMR (CDCl3, 300 MHz): δ = 7.62 (d, J = 9.00 Hz, 2H), 7.38 (s, 1H), 7.00 (d, J = 9.00 Hz,
2H), 3.86 (s, 3H), 2.53 (s, 3H), 1.38 (s, 9H). 13C-NMR (CDCl3, 75 MHz): δ = 207.7, 159.5, 140.3, 138.1, 136.7, 136.7, 134.2, 127.7, 127.1,
121.1, 114.5, 55.5, 45.0, 27.1, 22.1.
IR (Diamond ATR, neat): ν~ = 2960 (w), 2942 (w), 2930 (w), 2921 (w), 2901 (vw), 2832 (vw),
1690 (s), 1607 (m), 1575 (w), 1525 (m), 1480 (m), 1459 (m), 1451 (m), 1437 (w), 1424 (m), 1419
(m), 1392 (w), 1365 (w), 1360 (w), 1336 (w), 1313 (w), 1307 (w), 1291 (m), 1249 (vs), 1212 (m),
1179 (s), 1143 (m), 1116 (m), 1110 (m), 1033 (s), 1005 (w), 988 (m), 971 (m), 946 (w), 931 (w),
873 (m), 854 (m), 837 (vs), 815 (m), 800 (w), 789 (m), 771 (vw), 757 (vs), 735 (w), 715 (m), 696
(vw), 690 (w).
MS (EI, 70 eV): m/z = 376 (35) [M+], 319 (100), 276 (9), 261 (6), 57(6).
HR-MS: (C19H20O2S3) calculated: 376.0625 found: 376.0623.
1-(2-(4-Chlorobenzoyl)-6-(4-methoxyphenyl)thieno[3,2-b]thiophen-3-yl)-2,2-dimethylpro-
pan-1-one (7f)
S
S
t-BuOC
OMe
O
p-C6H4Cl
Prepared according to TP1 from 6g (826 mg, 2.5 mmol) and TMPMgCl· LiCl (2.39 mL, 1.15 M
in THF, 2.75 mmol). Deprotonation time: 20 min at -50 °C. An acylation reaction was perfomed
according to TP4 using 4-chlorobenzoyl chloride (525 mg, 3.0 mmol) at -50 °C during 2 h. Flash
column chromatographical purification on silica gel (pentane/CH2Cl2 = 3:2) afforded 7f (907 mg,
77%) as a light green solid.
Mp. : 162.9-164.3 °C. 1H-NMR (CDCl3, 300 MHz): δ = 7.88 (d, J = 9.00 Hz, 2H), 7.65 (s, 1H), 7.63 (d, J = 8.82 Hz,
2H), 7.48 (d, J = 9.00 Hz, 2H), 7.01 (d, J = 8.82 Hz, 2H), 3.86 (s, 3H), 1.35 (s, 9H). 13C-NMR (CDCl3, 75 MHz): δ = 210.4, 186.5, 159.8, 143.1, 141.5, 139.4, 138.3, 136.3, 136.2,
134.5, 130.7, 128.9, 127.8, 126.8, 126.2, 114.7, 55.5, 45.4, 27.4.
IR (Diamond ATR, neat): ν~ = 3081 (w), 2968 (w), 2959 (w), 2942 (w), 2930 (w), 2905 (w),
2871 (w), 2832 (vw), 2361 (w), 2340 (w), 2335 (w), 1697 (s), 1635 (s), 1611 (m), 1591 (m), 1576
(w), 1526 (m), 1483 (s), 1461 (m), 1439 (w), 1427 (w), 1397 (s), 1368 (w), 1358 (w), 1347 (w), 1325
(s), 1311 (w), 1303 (w), 1290 (m), 1277 (s), 1268 (s), 1253 (vs), 1232 (m), 1224 (m), 1195 (w), 1180
(s), 1160 (m), 1114 (w), 1109 (w), 1088 (s), 1070 (m), 1030 (s), 1016 (m), 957 (s), 949 (m), 893 (s),
848 (m), 837 (vs), 832 (vs), 816 (m), 795 (m), 779 (vs), 757 (s), 742 (m), 729 (m), 719 (w), 693 (w),
690 (m).
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
76
MS (EI, 70 eV): m/z = 468 (20) [M+], 412 (100), 377 (21), 361 (7), 139 (14), 111 (10).
HR-MS: (C25H21ClO3S2) calculated: 468.0621 found: 468.0615.
Ethyl 2-bromo-6-(butylthio)thieno[3,2-b]thiophene-3-carboxylate (7g)
Prepared according to TP1 from 6d (901 mg, 3.0 mmol) and TMPMgCl· LiCl (2.87 mL, 1.15 M
in THF, 3.3 mmol). Deprotonation time: 30 min at -20 °C. 1,2-dibromotetrachloroethane (1.17 g,
3.6 mmol) was added at -20 °C and the reaction mixture stirred for 2 h. The reaction mixture was
quenched with half concentrated aqueous NH4Cl solution, extracted three times with Et2O, dried
(MgSO4) and concentrated in vacuo. Flash column chromatographical purification on silica gel
(pentane/CH2Cl2 = 4:1) afforded 7g (1.03 g, 90%) as a pale yellow solid.
Mp. : 56.8-58.6 °C. 1H-NMR (C6D6, 300 MHz): δ = 6.89 (s, 1H), 4.05 (q, J = 7.12 Hz, 2H), 2.53 (t, J = 7.99 Hz,
2H), 1.36 (m, 2H), 1.17 (m, 2H), 1.02 (t, J = 7.12 Hz, 3H), 0.71 (t, J = 7.88 Hz, 3H). 13C-NMR (C6D6, 75 MHz): δ = 160.2, 139.4, 138.1, 128.5, 125.2, 123.7, 121.2, 60.9, 34.3, 31.5,
21.4, 13.8, 13.3.
IR (Diamond ATR, neat): ν~ = 2961 (m), 2942 (w), 2925 (w), 2898 (w), 2872 (w), 2861 (w),
1709 (s), 1668 (w), 1494 (s), 1473 (w), 1465 (m), 1450 (m), 1445 (m), 1391 (w), 1379 (w), 1324
(w), 1218 (vs), 1161 (w), 1102 (w), 1062 (s), 1025 (m), 979 (m), 937 (m), 842 (w), 822 (w), 772
(m), 700 (s).
MS (EI, 70 eV): m/z = 380 (80) [M+], 324 (100), 320 (34), 296 (24), 243 (13), 215 (24).
HR-MS: (C13H15O2Br1S3) calculated: 377.9418 found: 377.9418.
Ethyl 6-(methylthio)-5-pivaloyl-2-(4-(trifluoromethyl)phenyl)thieno[3,2-b]thiophene-3-
carboxylate (8a)
Prepared according to TP1 from 7b (509 mg, 1.3 mmol) and TMPMgCl· LiCl (1.22 mL, 1.15 M
in THF, 1.42 mmol). Deprotonation time: 15 min at 0 °C. An acylation reaction was perfomed
according to TP4 using pivaloyl chloride (193 mg, 1.6 mmol) at 0°C during 2 h. Flash column
chromatographical purification on silica gel (pentane/CH2Cl2 = 2:1) afforded 8a (508 mg, 80%)
as a pale yellow oil.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
77
Mp. : 166.2-167.9 °C. 1H-NMR (C6D6, 400 MHz): δ = 7.34 (d, J = 8.09 Hz, 2H), 7.23 (d, J = 8.09 Hz, 2H), 3.90 (q, J
= 7.12 Hz, 2H), 2.31 (s, 3H), 1.35 (s, 9H), 0.78 (t, J = 7.12 Hz, 3H). 13C-NMR (C6D6, 100 MHz): δ = 199.3, 161.2, 152.9, 141.9, 137.6, 137.0, 135.8, 134.6, 131.1 (q, J
= 32.2 Hz), 130.8, 125.0 (q, J = 4.0 Hz), 124.7 (q, J = 272 Hz), 122.0, 61.2, 44.4, 27.6, 17.4, 13.7.
IR (Diamond ATR, neat): ν~ = 2983 (w), 2964 (w), 1689 (m), 1624 (m), 1616 (m), 1493 (w),
1476 (w), 1465 (w), 1438 (m), 1405 (m), 1388 (w), 1370 (w), 1318 (s), 1275 (s), 1207 (m), 1188
(m), 1162 (vs), 1134 (vs), 1110 (s), 1067 (m), 1044 (s), 1014 (m), 990 (s), 954 (w), 947 (w), 921
(m), 872 (w), 852 (w), 842 (w), 833 (m), 794 (w), 780 (m), 760 (w), 756 (w), 736 (w), 697 (w), 661
(w).
MS (EI, 70 eV): m/z = 486 (11) [M+], 429 (100), 410 (14), 327 (4), 311 (4), 213 (5).
HR-MS: (C22H21O3F3S3) calculated: 486.0605 found: 486.0594.
Ethyl 5-(4-fluorophenyl)-6-(methylthio)-2-pivaloylthieno[3,2-b]thiophene-3-carboxylate
(8b)
Prepared according to TP1 from 7c (649 mg, 1.9 mmol) and TMPMgCl· LiCl (1.83 mL, 1.15 M in
THF, 2.1 mmol). Deprotonation time: 15 min at -40 °C. A cross coupling reaction was
performed according to TP3 using 1-Fluoro-4-iodobenzene (511 mg, 2.3 mmol) and Pd(dba)2
(34 mg, 3%) and tfp (28 mg, 6%) during 2 h at 25 °C. Flash column chromatographical puri-
fication on silica gel (pentane/CH2Cl2 = 2:1) afforded 7c (675 mg, 81%) as a light brown solid.
Mp. : 112.1-113.4 °C. 1H-NMR (C6D6, 300 MHz): δ = 7.47 (m, 2H), 6.80 (m, 2H), 4.01 (q, J = 7.12 Hz, 2H), 1.85 (s,
3H), 1.28 (s, 9H), 0.98 (t, J = 7.12 Hz, 3H). 13C-NMR (C6D6, 75 MHz): δ = 204.4, 163.2 (d, J = 248 Hz), 161.2, 147.0, 146.7, 142.1, 135.7,
131.4 (d, J = 8.0 Hz), 130.1 (d, J = 4.0 Hz), 124.5, 120.7, 115.8 (d, J = 16.1 Hz), 61.6, 45.1, 26.8,
17.6, 14.0.
IR (Diamond ATR, neat): ν~ = 2962 (w), 2929 (w), 2918 (w), 2903 (w), 2863 (vw), 1717 (vs),
1686 (s), 1650 (w), 1601 (w), 1515 (m), 1507 (s), 1485 (w), 1472 (m), 1459 (m), 1447 (m), 1440
(m), 1406 (w), 1389 (w), 1373 (w), 1363 (w), 1357 (w), 1262 (s), 1247 (s), 1239 (s), 1226 (vs), 1195
(m), 1149 (s), 1113 (m), 1106 (w), 1038 (m), 1028 (m), 1014 (m), 1006 (m), 990 (m), 976 (m), 960
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
78
(w), 952 (w), 938 (w), 927 (m), 895 (m), 872 (w), 842 (m), 829 (s), 815 (m), 780 (w), 760 (w), 749
(m), 678 (w), 672 (w).
MS (EI, 70 eV): m/z = 436 (34) [M+], 379 (83), 351 (100), 245 (11), 139 (10).
HR-MS: (C21H21O3F1S3) calculated: 436.0637 found: 436.0630.
Ethyl 3-(4-methoxyphenyl)-5-(methylthio)-6-pivaloylthieno[3,2-b]thiophene-2-
carboxylate (8c)
Prepared according to TP1 from 7e (377 mg, 1.0 mmol) and TMPMgCl· LiCl (0.96 mL, 1.15 M in
THF, 1.1 mmol). Deprotonation time: 2 h at 0 °C. Ethyl cyanoformate (119 mg, 1.2 mmol) was
added at 0 °C and the reaction mixture stirred for 1 h. The reaction mixture was quenched with
half concentrated aqueous NH4Cl solution, extracted three times with Et2O, dried (MgSO4) and
concentrated in vacuo. Flash column chromatographical purification on silica gel (pentane/CH2Cl2
= 2:1) afforded 8c (363 mg, 81%) as a white solid.
Mp. : 127.0-128.3 °C. 1H-NMR (CDCl3, 300 MHz): δ = 7.50 (d, J = 9.00 Hz, 2H), 7.00 (d, J = 9.00 Hz, 2H), 4.26 (q, J
= 7.13 Hz, 2H), 3.87 (s, 3H), 2.52 (s, 3H), 1.42 (s, 9H), 1.27 (t, J = 7.13 Hz, 3H). 13C-NMR (CDCl3, 75 MHz): δ = 205.1, 162.3, 160.0, 150.9, 140.4, 139.8, 138.2, 133.2, 130.5,
126.5, 126.1, 113.8, 61.3, 55.4, 44.5, 26.9, 20.7, 14.3.
IR (Diamond ATR, neat): ν~ = 2984 (w), 2959 (w), 1703 (s), 1629 (m), 1609 (m), 1533 (w),
1492 (m), 1474 (w), 1464 (w), 1457 (w), 1447 (w), 1442 (w), 1421 (m), 1406 (m), 1396 (m), 1369
(w), 1365 (w), 1339 (w), 1317 (w), 1305 (w), 1296 (w), 1286 (w), 1261 (s), 1249 (vs), 1178 (m),
1168 (s), 1127 (m), 1109 (m), 1079 (m), 1040 (m), 1025 (s), 1012 (m), 957 (w), 945 (w), 939 (w),
917 (w), 899 (w), 890 (w), 842 (m), 830 (m), 808 (w), 795 (w), 760 (m), 737 (w), 729 (w), 723 (w),
697 (w).
MS (EI, 70 eV): m/z = 448 (30) [M+], 391 (100), 320 (3), 275 (4), 57 (4).
HR-MS: (C22H24O4S3) calculated: 448.0837 found: 448.0821.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
79
Diethyl 2,5-dipivaloylthieno[3,2-b]thiophene-3,6-dicarboxylate (8d)
Prepared according to TP1 from 6b (569 mg, 2.0 mmol) and TMPMgCl· LiCl (1.91 mL, 1.15 M
in THF, 2.2 mmol). Deprotonation time: 20 min at -40 °C. An acylation reaction was perfomed
according to TP4 using pivaloyl chloride (580 mg, 4.4 mmol) at -40 °C during 1 h. Flash column
chromatographical purification on silica gel (pentane/CH2Cl2 = 1:1) afforded 8d (650 mg, 72%)
as a white solid.
Mp. : 162.8-163.5 °C. 1H-NMR (C6D6, 300 MHz): δ = 3.96 (q, J = 7.13 Hz, 4H), 1.22 (s, 18H), 0.93 (t, J = 7.13 Hz,
6H). 13C-NMR (C6D6, 75 MHz): δ = 204.3, 161.0, 150.0, 136.4, 123.1, 61.7, 45.1, 26.6, 14.0.
IR (Diamond ATR, neat): ν~ = 1460 (w), 1445 (w), 1408 (w), 1390 (w), 1384 (w), 1364 (w),
1300 (w), 1261 (w), 1232 (s), 1170 (m), 1141 (vs), 1112 (m), 1094 (m), 1033 (m), 1022 (m), 1015
(m), 970 (m), 943 (w), 917 (m), 853 (m), 816 (w), 809 (w), 780 (w), 768 (w), 756 (w), 680 (m).
MS (EI, 70 eV): m/z = 452 (2) [M+], 395 (42), 367 (41), 255 (6), 58 (31), 43 (100).
HR-MS: (C22H28O6S2) calculated: 452.1327 found: 452.1323.
Diethyl 2,5-bis(2-(ethoxycarbonyl)allyl)thieno[3,2-b]thiophene-3,6-dicarboxylate (8e)
Prepared according to TP1 from 6b (569 mg, 2.0 mmol) and TMPMgCl· LiCl (1.91 mL, 1.15 M
in THF, 2.2 mmol). Deprotonation time: 20 min at -40 °C. An allylation reaction was perfomed
according to TP4 using ethyl 2-(bromomethyl)acrylate (580 mg, 4.4 mmol) at -40 °C during 1 h.
Flash column chromatographical purification on silica gel (pentane/ethyl acetate = 4:1) afforded
8e (788 mg, 77%) as a white solid.
Mp. : 113.8-115.6 °C. 1H-NMR (C6D6, 400 MHz): δ = 6.28 (d, J = 1.24 Hz, 2H); 5.46 (d, J = 1.24 Hz, 2H); 4.43 (s,
4H), 4.05 (q, J = 7.12 Hz, 4H), 3.96 (q, J = 7.12 Hz, 4H), 1.02 (t, J = 7.12 Hz, 6H), 0.92 (t, J =
7.12 Hz, 6H). 13C-NMR (C6D6, 100 MHz): δ = 166.0, 162.0, 153.7, 139.3, 136.2, 126.6, 122.0, 60.9, 60.8, 32.41,
14.2, 14.1.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
80
IR (Diamond ATR, neat): ν~ = 2992 (w), 2980 (vw), 1715 (s), 1705 (vs), 1664 (vw), 1627 (w),
1510 (m), 1475 (w), 1467 (vw), 1454 (w), 1422 (w), 1408 (w), 1396 (vw), 1377 (w), 1365 (w), 1336
(w), 1283 (m), 1249 (vs), 1224 (m), 1144 (s), 1126 (s), 1111 (s), 1026 (s), 981 (w), 951 (w), 944 (m),
923 (w), 874 (m), 866 (w), 853 (m), 824 (w), 808 (w), 784 (m), 760 (vw), 698 (m), 671 (w).
MS (EI, 70 eV): m/z = 508 (100) [M+], 463 (32), 435 (98), 405 (53), 389 (52), 361 (35), 331 (20),
287 (19).
HR-MS: (C24H28O8S2) calculated: 508.1226 found: 508.1225.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
81
Direct Magnesium Insertion into Substituted 2,5-Dichlorothieno[3,2-b]thiophenes
Ethyl 5-chloro-2-(4-methoxyphenyl)-6-(methylthio)thieno[3,2-b]thiophene-3-carboxylate
(26a)
Prepared according to TP2 from 5a (982 mg, 3.0 mmol). Insertion time: 1h. A cross coupling
reaction was performed according to TP3 using 4-iodoanisole (702 mg, 3.0 mmol) and Pd(dba)2
(34 mg, 3%) and tfp (28 mg, 6%) during 3 h at 25 °C. Flash column chromatographical
purification on silica gel (pentane/CH2Cl2 = 2:1) afforded 26a (898 mg, 75%) as a yellow solid.
Mp. : 108.7-109.9 °C. 1H-NMR (CDCl3, 600 MHz): δ = 7.51 (m, 2H), 6.95 (m, 2H), 4.30 (q, J = 7.13 Hz, 2H), 3.86 (s,
3H), 2.48 (s, 3H), 1.31 (t, J = 7.13 Hz, 3H). 13C-NMR (CDCl3, 150 MHz): δ = 161.8, 160.6, 152.7, 137.1, 135.2, 133.6, 131.5, 125.3, 122.8,
120.7, 113.6, 61.2, 55.5, 17.6, 14.2.
IR (Diamond ATR, neat): ν~ = 2983 (w), 2925 (w), 2831 (w), 1716 (vs), 1671 (w), 1607 (m),
1572 (w), 1525 (m), 1487 (s), 1458 (m), 1439 (m), 1431 (m), 1414 (w), 1391 (m), 1365 (w), 1298
(m), 1267 (s), 1252 (vs), 1190 (s), 1172 (vs), 1113 (m), 1085 (w), 1061 (m), 1045 (m), 1031 (s),
1015 (s), 976 (w), 963 (w), 951 (w), 943 (w), 912 (m), 873 (w), 834 (s), 827 (m), 822 (m), 811 (m),
802 (w), 795 (m), 778 (s), 752 (w), 740 (m).
MS (EI, 70 eV): m/z = 398 (100) [M+], 370 (20), 355 (15), 185 (4).
HR-MS: (C17H15O3ClS3) calculated: 397.9872 found: 397.9857.
Ethyl 2-(4-(tert-butoxycarbonyl)phenyl)-5-chloro-6-(methylthio)thieno[3,2-b]thiophene-
3-carboxylate (26b)
Prepared according to TP2 from 5a (982 mg, 3.0 mmol). Insertion time: 1 h. A cross coupling
reaction was performed according to TP3 using tert-butyl 4-iodobenzoate (912 mg, 3.0 mmol)
and Pd(dba)2 (34 mg, 3%) and tfp (28 mg, 6%) during 2 h at 25 °C. Flash column chroma-
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
82
tographical purification on silica gel (pentane/CH2Cl2 = 2:1) afforded 26b (1.17 g, 83%) as a
yellow oil. 1H-NMR (CDCl3, 600 MHz): δ = 8.04 (d, J = 8.39 Hz, 2H), 7.60 (d, J = 8.39 Hz, 2H), 4.29 (q, J
= 7.13 Hz, 2H), 2.48 (s, 3H), 1.61 (s, 9H), 1.29 (t, J = 7.13 Hz, 3H). 13C-NMR (CDCl3, 150 MHz): δ = 165.3, 161.5, 150.7, 138.2, 137.0, 135.3, 134.6, 132.6, 130.0,
129.1, 122.9, 121.8, 81.4, 61.4, 28.3, 17.6, 14.2.
IR (Diamond ATR, neat): ν~ = 2977 (w), 2925 (w), 1710 (vs), 1694 (s), 1606 (w), 1487 (m),
1478 (w), 1454 (m), 1433 (w), 1403 (w), 1391 (w), 1367 (m), 1293 (vs), 1282 (s), 1262 (vs), 1203
(m), 1162 (vs), 1111 (vs), 1058 (m), 1037 (s), 1018 (s), 910 (m), 847 (m), 781 (w), 762 (s), 752 (m),
737 (m), 698 (m).
MS (EI, 70 eV): m/z = 468 (45) [M+], 412 (100), 395 (9), 384 (18), 369 (14), 183 (5).
HR-MS: (C21H21O4ClS3) calculated: 468.0290 found: 468.0284.
Ethyl 5-chloro-6-(4-chlorophenyl)-2-(4-methoxyphenyl)thieno[3,2-b]thiophene-3-
carboxylate (26c)
Prepared according to TP2 from 5g (1.18 g, 3.0 mmol). Insertion time: 2 h. A cross coupling
reaction was performed according to TP3 using 4-iodoanisole (702 mg, 3.0 mmol) and Pd(dba)2
(34 mg, 3%) and tfp (28 mg, 6%) during 2 h at 25 °C. Flash column chromatographical
purification on silica gel (pentane/CH2Cl2 = 2:1) afforded 26c (1.02 g, 74%) as a pale yellow
solid.
Mp. : 157.0-158.6 °C. 1H-NMR (C6D6, 400 MHz): δ = 7.45 (d, J = 8.80 Hz, 2H), 7.35 (d, J = 8.40 Hz, 2H), 7.14 (d, J
= 8.80 Hz, 2H), 6.74 (d, J = 8.40 Hz, 2H), 4.00 (q, J = 6.80 Hz, 2H), 3.25 (s, 3H), 0.92 (t, J = 6.80
Hz, 3H). 13C-NMR (C6D6, 100 MHz): δ = 161.6, 160.9. 152.3, 136.7, 134.6, 134.5, 131.8, 131.3, 130.0,
129.9, 129.3, 127.4, 125.6, 121.2, 113.8, 61.0, 54.8, 14.0.
IR (Diamond ATR, neat): ν~ = 2984 (vw), 2940 (vw), 2842 (vw), 1724 (s), 1490 (s), 1474 (m),
1280 (s), 1254 (vs), 1198 (s), 1176 (vs), 1028 (vs), 1010 (m), 892 (m), 830 (s), 822 (vs), 800 (m),
776 (s), 746 (m).
MS (EI, 70 eV): m/z = 462 (100) [M+], 436 (21), 419 (17), 311 (8), 300 (7).
HR-MS: (C22H16O3Cl2S2) calculated: 461.9918 found: 461.9912.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
83
Preparation of Fused Pyridazines
2,2-Dimethyl-1-(thieno[3,2-b]thiophen-2-yl)propan-1-one (27)
Prepared according to TP1 from thieno[3,2-b]thiophene73 (1.40 g, 10.0 mmol) and
TMPMgCl· LiCl (9.57 mL, 1.15 M in THF, 11.0 mmol). Deprotonation time: 1 h at 25 °C. An
acylation reaction was perfomed according to TP4 using pivaloyl chloride (1.45 g, 12.0 mmol) at
-20°C during 1 h. Flash column chromatographical purification on silica gel (pentane/CH2Cl2 =
2:1) afforded 27 (2.00 g, 89 %) as a white solid.
Mp. : 61.8-64.5 °C. 1H-NMR (C6D6, 300 MHz): δ = 7.45 (s, 1H), 6.86 (d, J = 5.26 Hz, 1H), 6.59 (d, J = 5.26 Hz,
1H), 1.16 (s, 9H). 13C-NMR (C6D6, 75 MHz): δ = 198.3, 145.3, 144.1, 139.4, 131.6, 124.1, 120.0, 43.6, 28.2.
IR (Diamond ATR, neat): ν~ = 3093 (w), 3077 (w), 2966 (w), 2955 (w), 2930 (w), 2926 (w),
2902 (w), 1764 (w), 1643 (s), 1628 (s), 1494 (m), 1475 (m), 1460 (w), 1447 (m), 1413 (m), 1395
(m), 1365 (w), 1346 (w), 1328 (s), 1293 (w), 1274 (m), 1217 (w), 1186 (s), 1141 (s), 1108 (m), 1094
(m), 1084 (w), 1071 (w), 1027 (w), 931 (m), 893 (w), 879 (m), 849 (w), 826 (w), 785 (m), 759 (w),
737 (m), 730 (vs), 704 (m).
MS (EI, 70 eV): m/z = 224 (17) [M+], 167 (100), 139 (11), 57 (10).
HR-MS: (C11H12OS2) calculated: 224.0330 found: 224.0322.
1,1'-(Thieno[3,2-b]thiophene-2,3-diyl)bis(2,2-dimethylpropan-1-one) (28a)
Prepared according to TP1 from 27 (1.57 g, 7.0 mmol) and TMPMgCl· LiCl (6.70 mL, 1.15 M in
THF, 7.7 mmol). Deprotonation time: 30 min at -50 °C. An acylation reaction was perfomed
according to TP4 using pivaloyl chloride (1.01 g, 8.4 mmol) at -40 °C during 2 h. The crude
product 28a (1.83 g, 87% purity by 1H-NMR, 74%) was obtained as a white solid which was used
in the next step without further purification. 1H-NMR (CDCl3, 300 MHz): δ = 6.78 (d, J = 5.32 Hz, 1H), 6.54 (d, J = 5.32 Hz, 1H), 1.40 (s,
9H), 1.21 (s, 9H).
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
84
13C-NMR (CDCl3, 75 MHz): δ = 209.1, 198.1, 143.1, 142.6, 137.1, 134.9, 132.6, 119.1, 45.0,
43.7, 27.7, 27.6.
MS (EI, 70 eV): m/z = 308 (3) [M+], 252 (100), 237 (94), 208 (10), 180 (7), 57 (8).
HR-MS: (C16H20O2S2) calculated: 308.0905 found: 308.0907.
5,8-Di-tert-butylthieno[2',3':4,5]thieno[2,3-d]pyridazine (29a)
Compound 28a (1.54 g, 5.0 mmol) was dissolved in ethanol (20 mL). Hydrazine hydrate (751 mg,
64%, 15.0 mmol) was added and the reaction mixture stirred for 12 h at 25 °C. The solvent was
evaporated and the reaction was quenched with half concentrated aqueous NH4Cl solution,
extracted three times with CH2Cl2, dried (MgSO4) and concentrated in vacuo. Flash column
chromatographical purification on silica gel (CH2Cl2) afforded 29a (1.45 g, 95 %) as a light yellow
solid.
Mp. : 198.2-200.9 °C. 1H-NMR (C6D6, 400 MHz): δ = 6.99 (d, J = 5.37 Hz, 1H), 6.73 (d, J = 5.37 Hz, 1H), 1.78 (s,
9H), 1.68 (s, 9H). 13C-NMR (C6D6, 150 MHz): δ = 162.7, 159.9, 141.5, 140.6, 133.0, 132.7, 129.7, 119.1, 38.8, 38.5,
29.4, 29.3.
IR (Diamond ATR, neat): ν~ = 3052 (m), 2966 (m), 2928 (m), 2904 (w), 2900 (w), 2868 (w),
1637 (m), 1497 (m), 1476 (m), 1418 (vs), 1399 (m), 1365 (s), 1348 (m), 1334 (m), 1278 (w), 1252
(w), 1220 (s), 1196 (s), 1160 (s), 1154 (s), 1109 (w), 1101 (w), 1075 (m), 1024 (w), 930 (m), 913
(vs), 883 (w), 858 (w), 835 (w), 803 (m), 797 (m), 785 (w), 767 (m), 749 (w), 738 (vs), 733 (vs), 710
(w), 702 (w), 690 (s), 674 (w), 669 (w), 666 (w), 658 (w).
MS (EI, 70 eV): m/z = 304 (9) [M+], 289 (29), 262 (100), 246 (13), 191 (7), 41 (5).
HR-MS: (C16H20N2S2) calculated: 304.1068 found: 304.1043.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
85
8-(4-Bromophenyl)-5-(tert-butyl)thieno[2',3':4,5]thieno[2,3-d]pyridazine (29b)
Prepared according to TP1 from 27 (1.57 g, 7.0 mmol) and TMPMgCl· LiCl (6.70 mL, 1.15 M in
THF, 7.7 mmol). Deprotonation time: 30 min at -50 °C. An acylation reaction was perfomed
according to TP4 using 4-bromobenzoyl chloride (1.85 g, 8.4 mmol) at -50 °C during 12 h while
warming the reaction mixture to room temperature. The reaction was quenched with half
concentrated aqueous NH4Cl solution, extracted three times with Et2O, dried (MgSO4) and
concentrated in vacuo. The crude product 28b was dissolved in ethanol (25 mL), hydrazine hydrate
(300 mg, 64%, 6.0 mmol) was added and the reaction mixture stirred for 12 h at 25 °C. The
solvent was evaporated and the reaction was quenched with half concentrated aqueous NH4Cl
solution, extracted three times with CH2Cl2, dried (MgSO4) and concentrated in vacuo. Flash
column chromatographical purification on silica gel (pentane/ethyl acetate = 10:1) afforded 29b
(2.04 g, 72 %) as a light yellow solid.
Mp. : 204.8-206.5 °C. 1H-NMR (CDCl3, 300 MHz): δ = 7.75 (m, 4H), 7.67 (d, J = 5.40 Hz, 1H), 7.45 (d, J = 5.40 Hz,
1H), 1.73 (s, 9H). 13C-NMR (CDCl3, 75 MHz): δ = 163.9, 152.2, 143.0, 140.9, 133.7, 132.8, 132.3, 130.7, 129.8,
125.0, 119.5, 38.9, 29.2. (Note: one signal corresponding to the quartenary carbon bound to the
phenyl ring and adjacent to a nitrogen atom in the pyridazine ring is very weak and broad, hence
not listed above. However, coupling in the HMBC spectrum was detected, and mass
spectrometry corresponds.)
IR (Diamond ATR, neat): ν~ = 3088 (vw), 2966 (w), 1590 (w), 1496 (w), 1468 (m), 1420 (m),
1396 (m), 1364 (m), 1348 (m), 1216 (m), 1086 (m), 1068 (s), 1008 (m), 888 (m), 842 (s), 836 (s),
818 (m), 804 (m), 790 (m), 748 (m), 718 (vs), 680 (s), 628 (m).
MS (EI, 70 eV): m/z = 403 (16) [M+], 389 (27), 362 (100), 267 (5), 165 (10).
HR-MS: (C18H15N2Br1S2) calculated: 401.9860 found: 401.9843.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
86
8-(tert-Butyl)-5-(4-chlorophenyl)-3-(4-methoxyphenyl)thieno[2',3':4,5]thieno[2,3-
d]pyridazine (29c)
Compound 7f (704 mg, 1.5 mmol) was dissolved in ethanol (10 mL). Hydrazine hydrate (225 mg,
64%, 4.5 mmol) was added and the reaction mixture stirred for 12 h at 25 °C. The solvent was
evaporated and the reaction was quenched with half concentrated aqueous NH4Cl solution,
extracted three times with CH2Cl2, dried (MgSO4) and concentrated in vacuo. Flash column
chromatographical purification on silica gel (pentane/CH2Cl2 = 1:1) afforded 29c (636 mg, 91 %)
as a light yellow solid.
Mp. : 242.6-244.0 °C. 1H-NMR (CDCl3, 300 MHz): δ = 8.05 (d, J = 8.70 Hz, 2H), 7.80 (s, 1H), 7.66 (d, J = 9.00 Hz,
2H), 7.56 (d, J = 8.70 Hz, 2H), 7.03 (d, J = 9.00 Hz, 2H), 3.87 (s, 3H), 1.79 (s, 9H). 13C-NMR (CDCl3, 75 MHz): δ = 160.7, 159.9, 154.5, 141.9, 136.4, 135.0, 134.7, 133.1, 130.0,
129.8, 129.3, 128.0, 127.8, 126.5, 114.8, 55.5, 38.5, 29.1.
IR (Diamond ATR, neat): ν~ = 3062 (w), 2984 (w), 2960 (w), 2926 (w), 2832 (vw), 1610 (w),
1596 (w), 1576 (w), 1528 (m), 1484 (m), 1452 (w), 1404 (m), 1392 (w), 1368 (w), 1294 (m), 1256
(s), 1228 (m), 1180 (m), 1086 (m), 1070 (w), 1036 (m), 1016 (m), 906 (w), 834 (vs), 784 (m), 764
(w), 744 (w), 724 (w).
MS (EI, 70 eV): m/z = 464 (10) [M+], 449 (14), 422 (100), 232 (4), 224 (5), 211 (4).
HR-MS: (C25H21ON2ClS2) calculated: 464.0784 found: 464.0775.
1,4,6,9-Tetra-tert-butylpyridazino[4'',5'':4',5']thieno[2',3':4,5]thieno[2,3-d]pyridazine (30)
Prepared according to TP1 from 30P (777 mg, 2.0 mmol) and TMPMgCl· LiCl (1.91 mL, 1.15 M
in THF, 2.2 mmol). Deprotonation time: 30 min at -50 °C. An acylation reaction was perfomed
according to TP4 using pivaloyl chloride (290 mg, 2.4 mmol) at -50 °C during 12 h while
warming the reaction mixture to room temperature. The reaction was quenched with half
concentrated aqueous NH4Cl solution, extracted three times with Et2O, dried (MgSO4) and
concentrated in vacuo. The crude product was dissolved in ethanol (25 mL), hydrazine hydrate
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
87
(300 mg, 64%, 6.0 mmol) was added and the reaction mixture stirred for 12 h at 25 °C. The
solvent was evaporated and the reaction was quenched with half concentrated aqueous NH4Cl
solution, extracted three times with CH2Cl2, dried (MgSO4) and concentrated in vacuo. Flash
column chromatographical purification on silica gel (CH2Cl2) afforded 30 (709 mg, 76 %) as a
light yellow solid.
Mp. : 359.8-361.2 °C. 1H-NMR (CDCl3, 300 MHz): δ = 1.86 (s, 18H), 1.76 (s, 18H). 13C-NMR (CDCl3, 75 MHz): δ = 162.8, 161.1, 141.8, 135.2, 128.2, 38.9, 38.5, 29.7, 29.4.
IR (Diamond ATR, neat): ν~ = 2982 (m), 2966 (s), 2921 (m), 2904 (w), 2872 (w), 1500 (m),
1475 (s), 1456 (m), 1403 (s), 1368 (s), 1365 (s), 1328 (m), 1257 (m), 1220 (vs), 1195 (s), 1161 (s),
1067 (m), 932 (m), 909 (vs).
MS (EI, 70 eV): m/z = 468 (14) [M+], 453 (30), 426 (64), 384 (100), 219 (4).
HR-MS: (C26H36N4S2) calculated: 468.2381 found: 468.2384.
1-(5,8-Di-tert-butylthieno[2',3':4,5]thieno[2,3-d]pyridazin-2-yl)-2,2-dimethylpropan-1-one
(30P)
Prepared according to TP1 from 29a (1.22 g, 4.0 mmol) and TMPMgCl· LiCl (3.83 mL, 1.15 M in
THF, 4.4 mmol). Deprotonation time: 30 min at 25 °C. An acylation reaction was perfomed
according to TP4 using pivaloyl chloride (580 mg, 4.8 mmol) at -30 °C during 2 h. Flash column
chromatographical purification on silica gel (pentane/CH2Cl2 = 1:1) afforded 30P (1.11 g, 71 %)
as a pale yellow solid.
Mp. : 218.7-220.1 °C. 1H-NMR (C6D6, 300 MHz): δ = 7.46 (s, 1H), 1.74 (s, 9H), 1.69 (s, 9H), 1.22 (s, 9H). 13C-NMR (C6D6, 75 MHz): δ = 198.1, 162.7, 160.8, 149.0, 141.6, 140.7, 136.7, 129.0, 123.0,
44.0, 38.9, 38.6, 29.3, 29.2, 27.9.
IR (Diamond ATR, neat): ν~ = 3110 (vw), 2984 (w), 2967 (w), 2958 (w), 2928 (w), 2903 (vw),
2866 (vw), 1637 (s), 1509 (w), 1505 (w), 1491 (w), 1473 (m), 1464 (w), 1398 (w), 1366 (m), 1348
(w), 1338 (w), 1326 (w), 1277 (m), 1252 (w), 1216 (m), 1207 (w), 1195 (m), 1151 (vs), 1071 (m),
1050 (w), 939 (w), 926 (w), 907 (m), 882 (m), 858 (w), 836 (w), 786 (w), 755 (w), 738 (w), 720 (w),.
MS (EI, 70 eV): m/z = 388 (9) [M+], 373 (21), 346 (100), 331 (7), 289 (8), 261 (5).
HR-MS: (C21H28O1N2S2) calculated: 388.1643 found: 388.1634.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
88
Preparation of Thieno[3,2-b]thiophene Oligomers
Trihexyl(thieno[3,2-b]thiophen-2-yl)silane (31)
Prepared from thieno[3,2-b]thiophene73 (2.10 g, 15.0 mmol) and n-BuLi (6.6 mL, 2.39 M in
hexane, 15.8 mmol). Deprotonation time: 20 min at -30 °C. Chlorotri-n-hexylsilane (5.26 g, 16.5
mmol) was added at -80 °C and the reaction mixture stirred for 1 h at this temperature. The
reaction mixture was quenched with half concentrated aqueous NH4Cl solution, extracted three
times with Et2O, dried (MgSO4) and concentrated in vacuo. Flash column chromatographical
purification on silica gel (pentane) afforded 31 (5.75 g, 91%) as a yellow viscous oil. 1H-NMR (C6D6, 400 MHz): δ = 7.22 (s, 1H), 6.89 (d, J = 7.99 Hz, 1H), 6.85 (d, J = 7.99 Hz,
1H), 1.49 (m, 6H), 1.38 (m, 6H), 1.29 (m, 12H), 0.90 (m, 15H). 13C-NMR (C6D6, 100 MHz): δ = 145.2, 141.9, 141.1, 128.3, 126.6, 119.4, 33.8, 31.8, 24.2, 23.0,
14.3, 13.8.
IR (Diamond ATR, neat): ν~ = 2954 (m), 2918 (s), 2869 (m), 2852 (m), 1465 (w), 1456 (w),
1440 (w), 1408 (w), 1377 (w), 1341 (w), 1300 (w), 1189 (w), 1163 (w), 1100 (w), 1087 (w), 989 (s),
962 (w), 816 (m), 763 (m), 720 (m), 702 (vs).
MS (EI, 70 eV): m/z = 422 (73) [M+], 337 (100), 254 (86), 199 (52), 170 (49), 113 (60).
HR-MS: (C24H42S2Si) calculated: 422.2497 found: 422.2494.
2,5-Dibromothieno[3,2-b]thiophene (32)
Thieno[3,2-b]thiophene (1.4 g, 10 mmol) was dissolved in DMF (20 mL) at 0 °C. N-Bromo-
succinimide (3.56 g, 20 mmol) was added and the reaction mixture stirred for 3 h. Water (500
mL) was added and the mixture extracted three times with ether. The organic phase was washed
with water, dried (MgSO4) and concentrated in vacuo. Flash column chromatographical
purification on silica gel (pentane) afforded 32 (5.84 g, 98%) as a white solid (Note: store
compound under argon at -80 °C to avoid decomposition).
Mp. : 116.8-118.5 °C. 1H-NMR (CDCl3, 300 MHz): δ = 6.31 (s, 2H). 13C-NMR (CDCl3, 75 MHz): δ = 138.5, 122.1, 113.7.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
89
IR (Diamond ATR, neat): ν~ = 3088 (w), 1618 (w), 1445 (vs), 1325 (m), 1156 (s), 1001 (s), 840
(s), 803 (vs).
MS (EI, 70 eV): m/z = 298 (100) [M+], 217 (20), 138 (31), 93 (13), 69 (28), 60 (12).
HR-MS: (C6H2Br2S2) calculated: 295.7965 found: 295.7955.
5,5''-Bis(trihexylsilyl)-2,2':5',2''-terthieno[3,2-b]thiophene (33a)
Prepared according to TP1 from 31 (846 mg, 2.0 mmol) and TMPMgCl· LiCl (2.87 mL, 1.15 M in
THF, 3.3 mmol). Deprotonation time: 1 h at 25 °C. A cross-coupling reaction was performed
according to TP3 using 2,5-dibromothienothiophene 32 (298 mg, 1.0 mmol) and Pd(OAc)2 (12
mg, 2.5%) and S-Phos (41 mg, 5%) during 12 h at 25 °C. Flash column chromatographical
purification on silica gel (pentane) afforded 33a (425 mg, 43%) as a dark red oil. 1H-NMR (C6D6, 400 MHz): δ = 7.17 (d, J = 0.70 Hz, 2H), 7.06 (d, J = 0.70 Hz, 2H), 6.84 (s,
1H), 1.52 (m, 12H), 1.43 (m, 12H), 1.32 (m, 24H), 0.94 (m, 30H). 13C-NMR (C6D6, 100 MHz): δ = 145.6, 141.7, 140.5, 140.4, 139.8, 139.2, 126.6, 116.4, 116.2,
33.8, 31.9, 24.3, 23.1, 14.4, 13.8.
IR (Diamond ATR, neat): ν~ = 2953 (m), 2917 (s), 2869 (m), 2851 (s), 1465 (m), 1456 (m),
1436 (m), 1408 (w), 1376 (w), 1308 (w), 1301 (w), 1170 (m), 1099 (w), 992 (vs), 949 (m), 940 (w),
882 (m), 822 (w), 800 (m), 768 (s), 719 (m), 695 (s).
MS (EI, 70 eV): m/z = 980 (100) [M+], 727 (20), 445 (10), 321 (11), 279 (20), 237 (53).
HR-MS: (C54H84S6Si2) calculated: 980.4435 found: 980.4434.
UV/Vis (CHCl3): λmax = 413 nm.
3,3''-Bis(butylthio)-2,2':5',2''-terthieno[3,2-b]thiophene (33b)
Prepared according to TP6 from 34 (307 mg, 1.0 mmol) and i-PrMgCl· LiCl (0.85 mL, 1.30 M in
THF, 1.1 mmol). Metallation time: 20 min at -50 °C. A cross-coupling reaction was performed
according to TP3 using 2,5-dibromothienothiophene 32 (164 mg, 0.5 mmol) and PEPPSI-iPr (19
mg, 2.5%) during 16 h at 60 °C in THF/NMP = 8:1. Flash column chromatographical
purification on silica gel (pentane) afforded 33b (142 mg, 48 %) as a very light and air sensitive
yellow solid.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
90
1H-NMR (CDCl3, 600 MHz): δ = 7.62 (s, 2H), 7.40 (d, J = 5.18 Hz, 2H), 7.23 (d, J = 5.18 Hz,
2H), 2.95 (t, J = 7.26 Hz, 4H), 1.59 (m, 4H), 1.42 (m, 4H), 0.86 (t, J = 7.35 Hz, 6H). 13C-NMR (CDCl3, 150 MHz): δ = 145.5, 140.5, 140.2, 138.4, 135.0, 127.7, 120.1, 119.8, 118.4,
35.2, 32.1, 21.9, 13.7.
MS (EI, 70 eV): m/z = 592 (100) [M+], 535 (23), 478 (37), 446 (17).
HR-MS: (C26H24S8) calculated: 591.9644 found: 591.9638.
UV/Vis (CHCl3): λmax = 416 nm.
3,3''-Dibutoxy-2,2':5',2''-terthieno[3,2-b]thiophene (33c)
Prepared according to TP6 from 35 (350 mg, 1.2 mmol) and i-PrMgCl· LiCl (1.0 mL, 1.30 M in
THF, 1.3 mmol). Metallation time: 20 min at -50 °C. A cross-coupling reaction was performed
according to TP3 using 2,5-dibromothienothiophene 32 (179 mg, 0.6 mmol) and PEPPSI-iPr (35
mg, 4 %) during 16 h at 60 °C in THF/NMP = 8:1. Flash column chromatographical purification
on silica gel (pentane/CH2Cl2 = 6:1) afforded 33c (143 mg, 51 %) as a very light and air sensitive
orange solid. 1H-NMR (CDCl3, 300 MHz): δ = 7.52 (s, 2H), 7.37 (d, J = 5.18 Hz, 2H), 7.33 (d, J = 5.18 Hz,
2H), 4.43 (t, J = 6.53 Hz, 4H), 1.94 (m, 4H), 1.64 (m, 4H), 1.04 (t, J = 7.36 Hz, 6H). 13C-NMR (CDCl3, 75 MHz): δ = 127.7, 127.5, 120.4, 120.3, 119.9, 119.8, 119.7, 114.9, 114.7,
72.1, 32.2, 19.3, 14.0.
MS (EI, 70 eV): m/z = 560 (60) [M+], 503 (65), 447 (100), 336 (14), 71 (8), 57 (18).
HR-MS: (C26H24O2S6) calculated: 560.0101 found: 560.0077.
UV/Vis (CHCl3): λmax = 415 nm.
(6,6''-Bis(butylthio)-[2,2':5',2''-terthieno[3,2-b]thiophene]-5,5''-diyl)bis(trimethylsilane)
(33d)
Prepared according to TP1 from 36 (301 mg, 1.0 mmol) and TMPMgCl· LiCl (0.96 mL, 1.15 M in
THF, 1.1 mmol). Deprotonation time: 1 h at 25 °C. A cross-coupling reaction was performed
according to TP3 using 2,5-dibromothienothiophene 32 (164 mg, 0.5 mmol) and PEPPSI-iPr (15
mg, 2 %) during 16 h at 60 °C in THF/NMP = 8:1. Flash column chromatographical purification
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
91
on silica gel (pentane/CH2Cl2 = 6:1) afforded 26 (173 mg, 47 %) as a very light and air sensitive
yellow solid. 1H-NMR (C6D6, 600 MHz): δ = 7.33 (s, 2H), 7.32 (s, 2H), 2.94 (q, J = 7.43 Hz, 4H), 1.62 (m,
4H), 1.45 (m, 4H), 0.92 (t, J = 7.36 Hz, 6H), 0.45 (s, 18H). 13C-NMR (C6D6, 150 MHz): δ = 145.6, 144.6, 143.1, 139.9, 139.6, 138.9, 130.1, 116.3, 116.1,
34.9, 32.2, 22.1, 13.8, 0.1.
MS (EI, 70 eV): m/z = 736 (100) [M+], 517 (8), 69 (11), 55 (11), 43 (7).
HR-MS: (C32H40S8Si2) calculated: 736.0434 found: 736.0432.
UV/Vis (CHCl3): λmax = 413 nm.
Diethyl 6,6''-bis(butylthio)-[2,2':5',2''-terthieno[3,2-b]thiophene]-3,3''-dicarboxylate (33e)
2,5-dibromothienothiophene 32 (164 mg, 0.55 mmol) was dissolved in THF (5.0 mL) and cooled
to -30 °C. Then n-BuLi (0.47 mL, 2.55 M in hexane, 1.2 mmol) was added and the reaction
mixture stirred for 15 min at that temperature. A cross-coupling reaction was performed
according to TP3 using compound 7g (380 mg, 1.0 mmol) and PEPPSI-iPr (15 mg, 4 %) during
12 h at 55 °C in THF/NMP = 8:1. Flash column chromatographical purification on silica gel
(pentane/CH2Cl2 = 2:1) afforded 33e (160 mg, 43 %) as a dark red solid.
Mp. : 147.4-149.4 °C. 1H-NMR (C6D6, 300 MHz): δ = 7.79 (s, 2H), 7.34 (s, 2H), 4.42 (q, J = 7.02 Hz, 4H), 2.92 (t, J =
7.79 Hz, 4H), 1.61 (m, 4H), 1.42 (m, 4H), 1.46 (t, J = 7.02 Hz, 6H), 0.92 (t, J = 7.79 Hz, 6H). 13C-NMR (C6D6, 75 MHz): δ = 161.8, 145.2, 141.2, 140.6, 138.9, 137.1, 129.4, 123.9, 121.9,
121.4, 61.5, 34.7, 31.8, 21.8, 14.4, 13.7.
IR (Diamond ATR, neat): ν~ = 2973 (w), 2950 (w), 2923 (w), 2867 (w), 2857 (w), 1721 (m),
1708 (s), 1484 (m), 1464 (m), 1439 (m), 1364 (w), 1333 (w), 1267 (w), 1234 (vs), 1206 (m), 1178
(s), 1137 (s), 1109 (m), 1021 (s), 979 (m), 942 (m), 855 (w), 846 (w), 828 (w), 821 (w), 777 (m), 749
(m), 741 (m), 717 (w), 663 (w).
MS (EI, 70 eV): m/z = 736 (100) [M+], 648 (21), 598 (7), 567 (6), 57 (7).
HR-MS: (C32H32O4S8) calculated: 736.0066 found: 736.0052.
UV/Vis (CHCl3): λmax = 416 nm.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
92
2-Bromo-3-(butylthio)thieno[3,2-b]thiophene (34)
Compound 34P (637 mg, 3.0 mmol) was dissolved in DMF (10 mL) and cooled to 0 °C. N-
Bromosuccinimid (545 mg, 3.0 mmol) was added and the reaction mixture stirred for 3 h at 0 °C.
Water was added and the mixture extracted three times with ether. The organic phase was
washed 4 times with water, dried (MgSO4) and concentrated in vacuo. Flash column
chromatographical purification on silica gel (pentane) afforded 34 (1.74 g, 94%) as a colorless oil. 1H-NMR (C6D6, 400 MHz): δ = 6.73 (d, J = 5.27 Hz, 1H), 6.46 (d, J = 5.27 Hz, 1H), 2.68 (t, J =
7.81 Hz, 2H), 1.35 (m, 2H), 1.19 (m, 2H), 0.68 (t, J = 7.32 Hz, 3H). 13C-NMR (C6D6, 100 MHz): δ = 142.3, 136.7, 126.7, 125.7, 119.8, 119.1, 34.2, 32.2, 21.7, 13.6.
IR (Diamond ATR, neat): ν~ = 2954 (m), 2925 (m), 2868 (w), 2858 (w), 1473 (w), 1462 (m),
1455 (w), 1431 (m), 1414 (w), 1377 (w), 1337 (s), 1310 (w), 1270 (w), 1222 (w), 1187 (m), 1085
(w), 1020 (m), 902 (s), 886 (m), 790 (m), 704 (vs).
MS (EI, 70 eV): m/z = 306 (52) [M+], 252 (81), 185 (11), 171 (100), 127 (16), 93 (11).
HR-MS: (C10H11BrS3) calculated: 305.9206 found: 305.9191.
3-(Butylthio)thieno[3,2-b]thiophene (34P)
Prepared according to TP6 from 3-bromothieno[3,2-b]thiophene73 (3.29 g, 15.0 mmol) and
i-PrMgCl· LiCl (12.7 mL, 1.30 M in THF, 16.5 mmol). Metalation time: 3 h at -30 °C. PhSO2SBu
(4.15 g, 18.0 mmol) was added at -30 °C and the reaction mixture stirred for 4 h while warming
to room temperature. The reaction mixture was quenched with half concentrated aqueous NH4Cl
solution, extracted three times with Et2O, dried (MgSO4) and concentrated in vacuo. Flash column
chromatographical purification on silica gel (pentane) afforded 17a (2.81 g, 82%) as a slightly
greenish oil. 1H-NMR (C6D6, 400 MHz): δ = 6.89 (d, J = 1.54 Hz, 1H), 6.80 (dd, J = 5.22 Hz, 1.54 Hz, 1H),
6.73 (d, J = 5.22 Hz, 1H), 2.65 (t, J = 7.34 Hz, 2H), 1.40 (m, 2H), 1.19 (m, 2H), 0.70 (t, J = 7.21
Hz, 3H). 13C-NMR (C6D6, 100 MHz): δ = 139.5, 133.3, 131.7, 131.2, 122.9, 119.6, 34.2, 32.2, 21.7, 13.6.
IR (Diamond ATR, neat): ν~ = 3097 (w), 2954 (m), 2925 (m), 2868 (w), 2858 (w), 1477 (w),
1463 (m), 1455 (m), 1435 (m), 1417 (w), 1377 (w), 1339 (m), 1322 (m), 1302 (w), 1295 (w), 1289
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
93
(w), 1271 (w), 1222 (w), 1187 (m), 1088 (m), 969 (s), 913 (w), 898 (m), 867 (w), 820 (s), 787 (m),
755 (w), 707 (vs), 696 (vs).
MS (EI, 70 eV): m/z = 228 (36) [M+], 185 (12), 172 (100), 127 (19), 96 (25), 69 (20).
HR-MS: (C10H12S3) calculated: 228.0101 found: 228.0092.
2-Bromo-3-butoxythieno[3,2-b]thiophene (35):
S
S
Br
BuO
Compound 35P (1.14 g, 5.0 mmol) was dissolved in DMF (20 mL) and cooled to 0 °C. NBS (908
mg, 5.0 mmol) was added and the reaction mixture stirred for 3 h at 0 °C. Water was added and
the mixture extracted three times with ether. The organic phase was washed 4 times with water,
dried (MgSO4) and concentrated in vacuo. Flash column chromatographical purification on silica
gel (pentane/CH2Cl2 = 8:1) afforded 35 (720 mg, 82%) as a colorless oil. 1H-NMR (CDCl3, 400 MHz): δ = 7.38 (d, J = 5.20 Hz, 1H), 7.12 (d, J = 5.20 Hz, 1H), 4.30 (t, J
= 6.47 Hz, 2H), 1.78 (m, 2H), 1.55 (m, 2H), 0.99 (t, J = 7.37 Hz, 3H). 13C-NMR (CDCl3, 100 MHz): δ = 147.5, 136.1, 129.5, 126.4, 120.1, 95.7, 72.3, 32.0, 19.2, 13.9.
IR (Diamond ATR, neat): ν~ = 2961 (m), 2923 (m), 2870 (w), 2858 (w), 1473 (w), 1458 (m),
1452 (w), 1429 (m), 1414 (w), 1381 (w), 1340 (s), 1310 (w), 1270 (w), 1222 (w), 1187 (m), 1085
(w), 1020 (m), 909 (s), 886 (m), 791 (m), 701 (vs).
MS (EI, 70 eV): m/z = 292 (26) [M+], 236 (100), 207 (10), 126 (14).
HR-MS: (C10H11OBrS2) calculated: 289.9435 found: 289.9431.
3-Butoxythieno[3,2-b]thiophene (35P)
Prepared according to a literature procedure from Buchwald.74 Cs2CO3 (4.9 g, 15.0 mmol), CuI
(144 mg, 1.0 mmol) and 3,4,7,8-tetramethyl-1,10-phenanthroline (473 mg, 2.0 mmol) were dired
on high vacuum for 2 h. Toluene (10 mL), dry butanol (1.11 g, 15 mmol) and 3-bromothieno[3,2-
b]thiophene73 (2.19 g, 10.0 mmol) were added and the reaction mixture was heated to 120 °C for
4 d. The reaction mixture was quenched with half concentrated aqueous NH4Cl solution,
extracted three times with Et2O, dried (MgSO4) and concentrated in vacuo. Flash column
74 R. A. Altman, A. Shafir, A. Choi, P. A. Lichtor, S. L. Buchwald, J. Org. Chem. 2008, 73, 284.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS THIENO[3,2-b]THIOPHENES
94
chromatographical purification on silica gel (pentane/CH2Cl2 = 8:1) afforded 35P (850 mg, 40%)
as a colorless oil. 1H-NMR (CDCl3, 300 MHz): δ = 7.35 (d, J = 5.15 Hz, 1H), 7.17 (d, J = 5.15 Hz, 1H), 6.27 (s,
1H), 4.09 (t, J = 6.47 Hz, 2H), 1.82 (m, 2H), 1.52 (m, 2H), 0.99 (t, J = 7.36 Hz, 3H). 13C-NMR (CDCl3, 75 MHz): δ = 150.1, 137.1, 130.9, 127.2, 120.2, 98.0, 70.3, 31.3, 19.3, 13.9.
IR (Diamond ATR, neat): ν~ = 3089 (w), 2959 (m), 2919 (m), 2868 (w), 2858 (w), 1477 (w),
1466 (m), 1451 (m), 1429 (m), 1420 (w), 1371 (w), 1341 (m), 1329 (m), 1300 (w), 1296 (w), 1289
(w), 1271 (w), 1222 (w), 1184 (m), 1089 (m), 972 (s), 913 (w), 898 (m), 867 (w), 821 (s), 787 (m),
755 (w), 709 (vs), 699 (vs).
MS (EI, 70 eV): m/z = 212 (37) [M+], 156 (100), 127 (11), 111 (6).
HR-MS: (C10H12OS2) calculated: 212.0330 found: 212.0319.
(3-(Butylthio)thieno[3,2-b]thiophen-2-yl)trimethylsilane (36)
Prepared according to TP6 from 34 (1.54 g, 5.0 mmol) and i-PrMgCl· LiCl (4.23 mL, 1.30 M in
THF, 5.5 mmol). Metallation time: 20 min at -50 °C. TMSCN (595 mg, 6.0 mmol) was added at
-50 °C and the reaction mixture stirred for 1 h while warming to room temperature. The reaction
mixture was quenched with half concentrated aqueous NH4Cl solution, extracted three times
with Et2O, dried (MgSO4) and concentrated in vacuo. Flash column chromatographical
purification on silica gel (pentane) afforded 36 (1.47 g, 97%) as a coloress oil. 1H-NMR (C6D6, 400 MHz): δ = 6.83 (d, J = 5.19 Hz, 1H), 6.78 (d, J = 5.19 Hz, 1H), 2.79 (t, J =
6.89 Hz, 2H), 1.46 (m, 2H), 1.20 (m, 2H), 0.71 (t, J = 7.35 Hz, 3H), 0.47 (s, 9H). 13C-NMR (C6D6, 100 MHz): δ = 146.3, 145.0, 143.3, 130.8, 128.5, 120.1, 34.9, 32.4, 22.2, 13.7,
0.1.
IR (Diamond ATR, neat): ν~ = 2954 (m), 2871 (w), 1474 (w), 1464 (w), 1435 (w), 1409 (w),
1340 (w), 1297 (w), 1270 (w), 1259 (w), 1245 (m), 1223 (w), 1190 (w), 1087 (w), 1028 (m), 872
(m), 834 (vs), 789 (m), 756 (m), 712 (m), 697 (m).
MS (EI, 70 eV): m/z = 300 (100) [M+], 285 (29), 244 (38), 229 (72), 213 (26), 185 (26) 153 (26).
HR-MS: (C13H20S3Si) calculated: 300.0496 found: 300.0486.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
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3.2 Benzo[b]thiophenes via Intramolecular Carbomagnesiation
Preparation of ortho-Dihaloarenes
1-Bromo-2-iodo-4-methoxybenzene (38a):
The title compound was prepared according to TP7 from 3-iodoanisole (50.0 mmol). Flash
column chromatographical purification on silica gel (pentane/CH2Cl2 = 6:1) afforded 38a (15.5 g,
99%) as a pale yellow oil. Analytical data corresponds to literature data.58
(4-Bromo-3-iodophenoxy)triisopropylsilane (38b):
Br
ITIPSO
The title compound was prepared according to TP7 from (3-iodophenoxy)triisopropylsilane
(60.0 mmol). 38b (26.7 g, 98%) was isolated as colorless oil and used without further purification. 1H-NMR (CDCl3, 300 MHz): δ = 7.39 (m, 2H), 6.71 (dd, J = 8.71 Hz, J = 2.84 Hz, 1H), 1.22
(m, 3H), 1.07 (m, 18H). 13C-NMR (CDCl3, 75 MHz): δ = 155.4, 132.5, 131.6, 121.2, 120.6, 100.8, 17.8, 12.6.
IR (Diamond ATR, neat): ν~ = 2942 (m), 2889 (w), 2865 (m), 1574 (s), 1545 (w), 1454 (vs),
1389 (w), 1384 (w), 1366 (w), 1278 (s), 1250 (m), 1227 (s), 1095 (m), 1070 (w), 1005 (m), 996 (m),
921 (vs), 881 (s), 865 (m), 812 (m), 747 (s), 681 (m), 660 (w).
MS (EI, 70 eV): m/z = 454 (29) [M+], 411 (100), 383 (33), 355 (46), 341 (19), 325 (20), 228 (15),
178 (19), 56 (21).
HR-MS: (C15H24OBrISi) calculated: 453.9824 found: 453.9813
2-Bromo-4-chloro-1-iodobenzene (38c):
The title compound was prepared according to TP8 from 4-chloroaniline (12.76 g, 100.0 mmol).
Flash column chromatographical purification on silica gel (pentane) afforded 38c (18.8 g, 59%) as
a white powder. Analytical data corresponds to literature data.58
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
96
3-Bromo-4-iodobenzonitrile (38d):
The title compound was prepared according to TP8 from 4-aminobenzonitrile (11.81 g, 84.0
mmol). Flash column chromatographical purification on silica gel (pentane/CH2Cl2 = 2:1)
afforded 38d (23.5 g, 91%) as an off white powder. Analytical data corresponds to literature
data.58
tert-Butyl 3-bromo-4-iodobenzoate (38e):
Precursor 38eP (100 mmol) was dissolved in THF (150 mL), aqueous NaOH (2 m, 75 mL) was
added at room temperature and the reaction mixture stirred for 2 h. The organic solvent was
removed in vacuo and the residue filtered, washed with water and dried to afford the crude 3-
bromo-4-iodobenzoic acid (29.6 g, 91%). The carboxylicacid was suspended in toluene (250 mL)
and SOCl2 (13.9 g, 1.30 equiv) was added in one portion at room temperature. The suspension
was refluxed for 2 h and stirred for further 12 h at room temperature. After cooling to -80 °C
KOt-Bu (15.2 g, 1.50 equiv) was added in small portions and the reaction mixture stirred for 12 h
while warming to room temperature. Water was added and the mixture extracted three times with
ether. The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo. Flash
column chromatographical purification on silica gel (pentane/diethyl ether = 8:1) afforded 38e
(27.9 g, 73% overall) as a colorless oil. 1H-NMR (CDCl3, 300 MHz): δ = 8.16 (d, J = 2.02 Hz, 1H), 7.90 (d, J = 8.25 Hz, 1H), 7.55 (dd,
J = 8.25 Hz, J = 2.02 Hz, 1H), 1.57 (s, 9H). 13C-NMR (CDCl3, 75 MHz): δ = 163.9, 140.2, 133.5, 133.2, 129.8, 128.9, 106.8, 82.1, 28.1.
IR (Diamond ATR, neat): ν~ = 2975 (w), 2930 (w), 1711 (vs), 1578 (m), 1550 (w), 1476 (w),
1451 (m), 1392 (m), 1365 (s), 1289 (vs), 1240 (s), 1160 (vs), 1136 (m), 1114 (vs), 1105 (s), 1057
(w), 1035 (w), 1005 (s), 901 (w), 878 (m), 846 (s), 755 (vs), 729 (m), 713 (w), 657 (w).
MS (EI, 70 eV): m/z = 382 (13) [M+], 328 (100), 309 (32), 75 (27), 57 (73), 41 (22).
HR-MS: (C11H12O2BrI) calculated: 381.9065 found: 381.9064.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
97
Ethyl 3-bromo-4-iodobenzoate (38eP):
The title compound was prepared according to TP8 from ethyl 4-aminobenzoate (100.0 mmol).
Flash column chromatographical purification on silica gel (pentane/diethyl ether = 6:1) afforded
38eP (26.3 g, 74%) as a pale yellow powder. Analytical data corresponds to literature data.58
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
98
Preparation of Organic Disulfides
1,2-Bis(2-bromo-5-methoxyphenyl)disulfane (41a):
The title compound was prepared according to TP9 from 38a (9.39 g, 30 mmol). Flash column
chromatographical purification on silica gel (pentane/diethyl ether = 3:1) afforded 41a (6.00 g,
91%) as a pale yellow oil. 1H-NMR (CDCl3, 300 MHz): δ = 7.38 (d, J = 8.77 Hz, 2H), 7.13 (d, J = 2.86 Hz, 2H), 6.62 (dd,
J = 8.77 Hz, J = 2.86 Hz, 2H), 3.71 (s, 6H). 13C-NMR (CDCl3, 75 MHz): δ = 159.6, 137.0, 133.4, 114.4, 112.6, 111.3, 55.5.
IR (Diamond ATR, neat): ν~ = 3000 (w), 2956 (w), 2933 (w), 2831 (w), 1577 (s), 1564 (s), 1458
(vs), 1428 (s), 1394 (m), 1377 (m), 1288 (s), 1258 (vs), 1231 (s), 1222 (vs), 1181 (m), 1143 (w),
1130 (w), 1091 (m), 1037 (s), 1009 (s), 862 (m), 843 (m), 796 (s), 684 (m).
MS (EI, 70 eV): m/z = 436 (67) [M+], 276 (100), 261 (16), 220(11), 138 (45), 123 (22).
HR-MS: (C14H12O2Br2S2) calculated: 433.8645 found: 433.8637.
1,2-Bis(2-bromo-5-((triisopropylsilyl)oxy)phenyl)disulfane (41b):
The title compound was prepared according to TP9 from 38b (13.65 g, 30 mmol). Flash column
chromatographical purification on silica gel (pentane) afforded 41b (8.52 g, 79%) as a yellow oil. 1H-NMR (CDCl3, 300 MHz): δ = 7.32 (d, J = 8.58 Hz, 2H), 6.99 (d, J = 2.86 Hz, 2H), 6.59 (dd,
J = 8.58 Hz, J = 2.86 Hz, 2H), 1.08 (m, 6H), 0.96 (m, 36H). 13C-NMR (CDCl3, 75 MHz): δ = 156.5, 135.8, 133.5, 120.1, 116.7, 110.8, 17.8, 12.6.
IR (Diamond ATR, neat): ν~ = 2943 (m), 2889 (w), 2865 (m), 1573 (s), 1557 (m), 1486 (m),
1456 (vs), 1446 (vs), 1383 (m), 1368 (w), 1274 (vs), 1262 (s), 1227 (s), 1093 (w), 1070 (w), 1014
(m), 995 (m), 938 (s), 919 (m), 881 (vs), 858 (m), 827 (w), 809 (m), 771 (vs), 731 (m), 684 (s), 673
(s).
MS (EI, 70 eV): m/z = 720 (21) [M+], 317 (20), 289 (12), 260 (11), 157 (100), 115 (41), 73(16), 59
(17).
HR-MS: (C30H48O2Br2S2Si2) calculated: 718.1001 found: 718.0991.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
99
1,2-Bis(2-bromo-4-chlorophenyl)disulfane (41c):
Br
S
Cl
Br
S
Cl
The title compound was prepared according to TP9 from 38c (9.52 g, 30 mmol). Flash column
chromatographical purification on silica gel (pentane) afforded 41c (5.20 g, 82%) as a pale yellow
powder.
Mp. : 105.9-106.7 °C. 1H-NMR (CDCl3, 300 MHz): δ = 7.57 (d, J = 2.18 Hz, 2H), 7.45 (d, J = 8.59 Hz, 2H), 7.27 (dd,
J = 8.59 Hz, J = 2.18 Hz, 2H). 13C-NMR (CDCl3, 75 MHz): δ = 134.6, 133.4, 132.6, 128.5, 128.1, 121.6.
IR (Diamond ATR, neat): ν~ = 3071 (vw), 2958 (w), 2922 (w), 2860 (w), 1576 (w), 1562 (w),
1544 (m), 1456 (w), 1438 (vs), 1410 (w), 1398 (w), 1375 (m), 1364 (s), 1312 (w), 1260 (w), 1242
(m), 1239 (m), 1152 (w), 1143 (w), 1132 (vw), 1114 (w), 1106 (w), 1095 (s), 1072 (w), 1050 (w),
1019 (s), 1000 (m), 950 (vw), 944 (vw), 861 (m), 858 (m), 809 (s), 777 (vs), 759 (m), 679 (vw), 664
(w).
MS (EI, 70 eV): m/z = 444 (100) [M+], 284 (25), 223 (95), 142 (37), 107 (40), 63 (29).
HR-MS: (C12H6Br2Cl2S2) calculated: 441.7655 found: 441.7650.
4,4'-Disulfanediylbis(3-bromobenzonitrile) (41d):
The title compound was prepared according to TP9 from 38d (9.24 g, 30 mmol). Flash column
chromatographical purification on silica gel (pentane/CH2Cl2 = 1:1) afforded 41d (3.59 g, 59%)
as a yellow powder.
Mp. : 226.8-288.2 °C. 1H-NMR (DMSO-d6/CDCl3, 300 MHz): δ = 7.82 (d, J = 1.49 Hz, 2H), 7.55 (dd, J = 8.31 Hz,
J = 1.49 Hz, 2H), 7.47 (d, J = 8.31 Hz, 2H). 13C-NMR (DMSO-d6/CDCl3, 75 MHz): δ = 141.2, 135.2, 131.2, 126.0, 120.2, 116.2, 111.1.
IR (Diamond ATR, neat): ν~ = 3072 (w), 2361 (w), 2358 (w), 2227 (m), 2217 (w), 2214 (w),
1739 (m), 1582 (w), 1534 (w), 1452 (s), 1436 (m), 1394 (w), 1374 (m), 1355 (m), 1257 (m), 1240
(w), 1230 (w), 1217 (w), 1209 (w), 1204 (w), 1191 (m), 1099 (w), 1022 (m), 904 (m), 887 (w), 828
(s), 820 (vs), 671 (w).
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
100
MS (EI, 70 eV): m/z = 426 (43) [M+], 266 (13), 213 (71), 134 (100), 84 (10), 69 (18).
HR-MS: (C14H6N2Br2S2) calculated: 423.8339 found: 423.8329.
Di-tert-butyl 4,4'-disulfanediylbis(3-bromobenzoate) (41e):
The title compound was prepared according to TP9 from 38e (11.49 g, 30 mmol). Flash column
chromatographical purification on silica gel (pentane/diethyl ether = 3:1) afforded 41e (4.46 g,
103%, impurities, which are mostly hydrolysis, do not affect the succeeding reaction) as a yellow
solid.
Mp. : 129.0-132.0 °C. 1H-NMR (CDCl3, 300 MHz): δ = 8.12 (d, J = 1.53 Hz, 2H), 7.84 (dd, J = 8.39 Hz, J = 1.53 Hz,
2H), 7.47 (d, J = 8.39 Hz, 2H), 1.55 (s, 18 H). 13C-NMR (CDCl3, 75 MHz): δ = 163.8, 140.7, 133.8, 131.9, 128.9, 125.9, 120.2, 81.8, 28.1.
IR (Diamond ATR, neat): ν~ = 2982 (w), 2968 (w), 2931 (w), 1708 (s), 1695 (s), 1582 (m), 1552
(w), 1472 (w), 1454 (m), 1392 (w), 1370 (s), 1364 (s), 1290 (vs), 1249 (s), 1236 (s), 1159 (vs), 1113
(vs), 1034 (w), 1019 (s), 979 (w), 930 (w), 912 (w), 878 (m), 846 (s), 828 (m), 773 (m), 765 (s), 758
(s), 748 (m), 734 (m), 720 (w), 668 (w), 662 (w).
MS (EI, 70 eV): m/z = 576 (15) [M+], 464 (43), 288 815), 234 (100), 217 (31), 153 (16), 108 (23),
57 (44), 41 (39).
HR-MS: (C22H24O4Br2S2) calculated: 573.9483 found: 573.9480.
1,2-Di(benzo[3,2-b]thiophen-3-yl)disulfane (41f):
The title compound was prepared according to TP9 from 3-bromobenzo[b]thiophene (6.39 g, 30
mmol). The crude product 41f (3.30 g, 100%; impurities, which are mostly hydrolysis, do not
affect the succeeding reaction) was used in the next step without further purification. Analytical
data corresponds to literature data.58
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
101
Preparation of Sulfonothioate Electrophiles
S-(2-bromo-5-methoxyphenyl) benzenesulfonothioate (42a):
The title compound was prepared according to TP10 from 41a (6.00 g, 13.8 mmol). Flash
column chromatographical purification on silica gel (pentane/ethyl acetate= 4:1) afforded 42a
(8.52 g, 86%) as a white powder.
Mp. : 94.3-95.6 °C. 1H-NMR (CDCl3, 300 MHz): δ = 7.64-7.55 (m, 3H), 7.47-7.38 (m, 2H), 7.42 (d, J = 8.92 Hz,
1H), 7.22 (d, J = 2.97 Hz, 1H). 6.87 (dd, J = 8.92 Hz, J = 2.97 Hz, 1H), 3.78 (s, 3H). 13C-NMR (CDCl3, 75 MHz): δ = 159.0, 143.4, 133.9, 133.9, 129.6, 129.0, 127.6, 123.4, 121.3,
119.9, 55.8.
IR (Diamond ATR, neat): ν~ = 3063 (w), 3003 (vw), 2955 (w), 2830 (w), 2360 (vw), 1581 (m),
1468 (s), 1447 (m), 1430 (m), 1374 (w), 1319 (s), 1307 (m), 1293 (s), 1286 (s), 1258 (m), 1232 (vs),
1187 (w), 1173 (w), 1141 (vs), 1103 (m), 1075 (s), 1069 (s), 1033 (s), 1021 (m), 1009 (m), 997 (m),
868 (w), 858 (m), 821 (s), 757 (s), 715 (vs), 687 (s).
MS (EI, 70 eV): m/z = 460 (47) [M+], 233 (46), 220 (100), 175 (13), 138 (98), 123 (54), 109 (17),
95 (35), 77 (74), 51 (27).
HR-MS: (C13H11O3BrS2) calculated: 357.9333 found: 357.9326.
S-(2-bromo-5-((triisopropylsilyl)oxy)phenyl) benzenesulfonothioate (42b):
The title compound was prepared according to TP10 from 41b (8.50 g, 11.8 mmol). Flash
column chromatographical purification on silica gel (pentane/diethyl ether = 5:1) afforded 42b
(8.42 g, 71%) as a colorless oil. 1H-NMR (CDCl3, 300 MHz): δ = 7.58 (m, 3H), 7.42 (m, 2H), 7.36 (d, J = 8.77 Hz, 1H), 7.26
(d, J = 3.06 Hz, 1H), 6.84 (dd, J = 8.77 Hz, J = 3.06 Hz, 1H), 1.33-1.21 (m, 3H), 1.11-1.09 (m,
18H). 13C-NMR (CDCl3, 75 MHz): δ = 155.8, 143.5, 133.9, 133.8, 130.2, 129.4, 129.0, 127.5, 124.8,
121.6, 17.8, 12.5.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
102
IR (Diamond ATR, neat): ν~ = 2943 (m), 2890 (w), 2865 (m), 1576 (m), 1447 (s), 1338 (m),
1327 (m), 1308 (m), 1280 (s), 1229 (m), 1144 (vs), 1100 (w), 1077 (m), 1015 (m), 997 (m), 941 (s),
880 (s), 820 (m), 767 (s), 752 (m), 715 (s), 681 (s).
MS (EI, 70 eV): m/z = 500 (7) [M+], 457 (22), 360 (31), 289 (44), 261 (68), 247 (36), 157 (66),
115 (31), 77 (100), 59 (33).
HR-MS: (C21H29O3BrS2Si) calculated: 500.0511 found: 500.0497.
S-(2-bromo-4-chlorophenyl) benzenesulfonothioate (42c):
The title compound was prepared according to TP10 from 41c (6.23 g, 14.0 mmol). Flash
column chromatographical purification on silica gel (pentane/diethyl ether = 4:1) afforded 42c
(9.00 g, 88%) as a white powder.
Mp. : 117.6-119.2 °C. 1H-NMR (CDCl3, 300 MHz): δ = 7.66-7.55 (m, 5H), 7.50-7.42 (m, 2H), 7.35 (dd, J = 8.44 Hz, J
= 2.20 Hz, 1H). 13C-NMR (CDCl3, 75 MHz): δ = 143.3, 139.9, 138.7, 134.1, 133.3, 131.6, 129.2, 128.7, 127.9,
127.5.
IR (Diamond ATR, neat): ν~ = 3088 (w), 3061 (w), 2969 V(w), 1560 (m), 1540 (w), 1445 (m),
1361 (m), 1326 (s), 1308 (s), 1298 (m), 1140 (vs), 1102 (m), 1092 (m), 1076 (s), 1056 (m), 1021
(m), 996 (m), 871 (m), 829 (m), 785 (m), 752 (s), 714 (vs), 683 (s).
MS (EI, 70 eV): m/z = 364 (12) [M+], 224 (52), 142 (47), 108 (30), 77 (100), 64 (28), 50 (23).
HR-MS: (C12H8O2BrClS2) calculated: 361.8838 found: 361.8847.
S-(2-bromo-4-cyanophenyl) benzenesulfonothioate (42d):
The title compound was prepared according to TP10 from 41d (3.10 g, 7.30 mmol). Flash
column chromatographical purification on silica gel (pentane/CH2Cl2 = 1:1) afforded 42d (4.93 g,
95%) as a pale yellow powder.
Mp. : 133.6-135.2 °C. 1H-NMR (CDCl3, 300 MHz): δ = 7.90-7.80 (m, 2H), 7.69-7.57 (m, 4H), 7.52-7.43 (m, 2H). 13C-NMR (CDCl3, 75 MHz): δ = 143.4, 139.3, 136.4, 135.3, 134.4, 131.2, 131.2, 129.3, 127.4,
116.3, 116.2.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
103
IR (Diamond ATR, neat): ν~ = 3080 (w), 3014 (w), 2228 (m), 1739 (m), 1734 (m), 1579 (m),
1576 (m), 1533 (m), 1452 (s), 1447 (vs), 1372 (s), 1331 (vs), 1309 (m), 1283 (w), 1280 (w), 1265
(m), 1257 (m), 1191 (m), 1179 (m), 1168 (m), 1147 (vs), 1098 (m), 1079 (s), 1069 (m), 1022 (s),
997 (m), 904 (m), 886 (m), 847 (s), 829 (s), 821 (vs), 756 (s), 715 (vs), 705 (m), 697 (m), 683 (vs),
671 (s).
MS (EI, 70 eV): m/z = 354 (5) [M+], 213 (22), 141 (69), 133 (32), 77 (100), 69 (18), 51 (29).
HR-MS: (C13H8O2NBrS2) calculated: 352.9180 found: 352.9184.
tert-Butyl 3-bromo-4-((phenylsulfonyl)thio)benzoate (42e):
The title compound was prepared according to TP10 from 41e (4.32 g, 7.50 mmol). Flash
column chromatographical purification on silica gel (pentane/diethyl ether = 2:1) afforded 42e
(4.93 g, 77%) as a white powder.
Mp. : 77.9-79.9 °C. 1H-NMR (CDCl3, 300 MHz): δ = 8.11 (d, J = 1.91 Hz, 1H), 7.96-7.89 (m, 1H), 7.76 (d, J = 8.01
Hz, 1H), 7.63-7.55 (m, 3H), 7.48-7.41 (m, 2H), 1.58 (s, 9H). 13C-NMR (CDCl3, 75 MHz): δ = 163.3, 143.5, 138.8, 135.9, 134.1, 133.5, 130.6, 129.2, 128.7,
127.4, 126.8, 82.6, 28.0.
IR (Diamond ATR, neat): ν~ = 3084 (m), 3060 (m), 2982 (m), 1714 (s), 1471 (m), 1446 (s),
1392 (m), 1365 (s), 1326 (s), 1306 (s), 1294 (s), 1285 (s), 1267 (s), 1255 (s), 1244 (s), 1175 (s), 1161
(s), 1147 (vs), 1119 (vs), 1077 (vs), 1056 (s), 1032 (s), 1022 (s), 998 (s), 970 (s), 905 (s), 880 (s), 848
(s), 841 (s), 780 (s), 765 (s), 749 (s), 715 (s), 697 (m), 683 (s).
MS (EI, 70 eV): m/z = 427 (2) [M+], 288 (16), 234 (100), 215 (32), 125 (26), 108 (26), 77 (54), 63
(13), 57 (40), 41 (30).
HR-MS: (C17H17O4BrS2) calculated: 427.9752 found: 427.9740.
S-benzo[b]thiophen-3-yl benzenesulfonothioate (42f):
The title compound was prepared according to TP10 from 41f (4.96 g, 15.0 mmol). Flash column
chromatographical purification on silica gel (pentane/diethyl ether = 6:1) afforded 42f (7.27 g,
79%) as a yellow powder.
Mp. : 63.8-65.3 °C.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
104
1H-NMR (CDCl3, 300 MHz): δ = 7.82 (d, J = 8.01 Hz, 1H), 7.70 (s, 1H), 7.57-7.45 (m, 4H),
7.38-7.27 (m, 4H). 13C-NMR (CDCl3, 75 MHz): δ = 142.9, 139.0, 138.6, 138.4, 133.7, 128.8, 127.4, 125.3, 125.1,
122.7, 122.5, 119.1.
IR (Diamond ATR, neat): ν~ = 3094 (w), 2363 (w), 1738 (m), 1734 (m), 1451 (m), 1445 (m),
1436 (w), 1416 (m), 1318 (s), 1304 (m), 1294 (m), 1252 (w), 1229 (w), 1217 (w), 1135 (vs), 1096
(m), 1087 (w), 1074 (s), 1070 (s), 1059 (m), 1031 (w), 1027 (w), 1024 (w), 1018 (m), 997 (m), 941
(w), 923 (w), 836 (m), 825 (m), 756 (s), 750 (s), 740 (m), 731 (s), 715 (vs), 702 (m), 682 (s).
MS (EI, 70 eV): m/z = 305 (10) [M+], 166 (100), 1334 (26), 121 (76), 110 (10), 77 (44), 64 (24),
50 (16).
HR-MS: (C14H10O2S3) calculated: 305.9843 found: 305.9851.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
105
Preparation of Alkynyl(aryl)thioethers
(((2-Bromo-5-methoxyphenyl)thio)ethynyl)trimethylsilane (9a):
The title compound was prepared according to TP11 from ethinyltrimethylsilane (3.26 g, 30.8
mmol, 1.30 equiv) i-PrMgCl· LiCl (22.0 mL, 1.29 M, 28.4 mmol, 1.20 equiv) and sulfonothioate
42a (8.52 g, 23.7 mmol, 1.00 equiv). Flash column chromatographical purification on silica gel
(pentane) afforded 9a (5.53 g, 74%) as a orange oil. 1H-NMR (CDCl3, 300 MHz): δ = 7.34 (d, J = 2.73 Hz, 1H), 7.27 (d, J = 8.67 Hz, 1H), 7.64 (dd,
J = 8.67 Hz, J = 2.73 Hz, 1H), 3.81 (s, 3H), 0.26 (s, 9H). 13C-NMR (CDCl3, 75 MHz): δ = 159.5, 134.9, 133.2, 114.3, 111.9, 110.0, 108.7, 89.8, 55.4, -0.2.
IR (Diamond ATR, neat): ν~ = 2958 (w), 2897 (vw), 2096 (m), 1574 (w), 1562 (w), 1446 (m),
1428 (m), 1249 (s), 1104 (w), 1036 (w), 1017 (m), 872 (vs), 838 (vs), 758 (s), 742 (vs), 706 (m).
MS (EI, 70 eV): m/z = 316 (78) [M+], 301(100), 219 (23), 205 (18), 175 (98), 145 (22), 134 (13),
115 (12), 73 (10), 63 (18).
HR-MS: (C12H15OBrSSi) calculated: 313.9796 found: 313.9800.
(4-Bromo-3-(((trimethylsilyl)ethynyl)thio)phenoxy)triisopropylsilane (9b):
The title compound was prepared according to TP11 from ethinyltrimethylsilane (926 mg, 9.43
mmol, 1.30 equiv) i-PrMgCl· LiCl (6.74 mL, 1.29 M, 8.70 mmol, 1.20 equiv) and sulfonothioate
42b (3.64 g, 7.25 mmol, 1.00 equiv). Flash column chromatographical purification on silica gel
(pentane) afforded 9b (2.42 g, 73%) as a colorless oil. 1H-NMR (CDCl3, 300 MHz): δ = 7.28 (d, J = 8.62 Hz, 1H), 7.24 (d, J = 2.75 Hz, 1H), 6.60 (dd,
J = 8.62 Hz, J = 2.75 Hz, 1H), 1.30-1.19 (m, 3H), 1.11 (s, 9H), 1.09 (s, 9H), 0.25 (s, 9H). 13C-NMR (CDCl3, 75 MHz): δ = 156.2, 134.7, 133.2, 119.5, 118.4, 110.2, 108.3, 89.7, 17.9, 12.6,
-0.2.
IR (Diamond ATR, neat): ν~ = 2957 (w), 2944 (m), 2866 (m), 2096 (w), 1574 (m), 1558 (w),
1459 (s), 1383 (w), 1283 (s), 1262 (m), 1249 (s), 1230 (m), 1097 (w), 1015 (w), 996 (w), 944 (s),
873 (vs), 841 (vs), 827 (m), 809 (m), 759 (s), 684 (m), 676 (m).
MS (EI, 70 eV): m/z = 456 (53) [M+], 413 (59), 371 (39), 334 (34), 291 (24), 172 (90), 157 (44),
73 (100), 59 (55).
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
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HR-MS: (C20H33OBrSSi2) calculated: 456.0974 found: 456.0975.
(((2-Bromo-4-chlorophenyl)thio)ethynyl)trimethylsilane (9c):
The title compound was prepared according to TP11 from ethinyltrimethylsilane (3.40 g, 34.5
mmol, 1.40 equiv) i-PrMgCl· LiCl (22.2 mL, 1.29 M, 29.7 mmol, 1.20 equiv) and sulfonothioate
42c (9.00 g, 24.7 mmol, 1.00 equiv). Flash column chromatographical purification on silica gel
(pentane) afforded 9c (6.47 g, 82%) as a colorless oil. 1H-NMR (CDCl3, 300 MHz): δ = 7.58 (d, J = 8.59 Hz, 1H), 7.50 (d, J = 2.15 Hz, 1H), 7.34 (dd,
J = 8.59 Hz, J = 2.15 Hz, 1H), 0.26 (s, 9H). 13C-NMR (CDCl3, 75 MHz): δ = 133.0, 132.5, 132.2, 128.4, 127.8, 119.7, 108.9, 89.0, -0.2.
IR (Diamond ATR, neat): ν~ = 2957 (w), 2098 (m), 1569 (w), 1547 (w), 1443 (m), 1405 (w),
1366 (w), 1261 (w), 1248 (s), 1144 (w), 1098 (m), 1021 (m), 871 (vs), 839 (vs), 827 (s), 808 (s), 781
(s), 757 (s), 716 (w), 700 (w), 683 (w).
MS (EI, 70 eV): m/z = 320 (50) [M+], 305 (82), 182 (24), 74 (82), 59 (100), 45 (37).
HR-MS: (C11H12BrClSSi) calculated: 317.9301 found: 317.9294.
3-Bromo-4-(((trimethylsilyl)ethynyl)thio)benzonitrile (9d):
The title compound was prepared according to TP11 from ethinyltrimethylsilane (1.18 g, 12.0
mmol, 1.30 equiv) i-PrMgCl· LiCl (22.2 mL, 1.26 M, 10.1 mmol, 1.10 equiv) and sulfonothioate
42d (3.27 g, 9.20 mmol, 1.00 equiv). Flash column chromatographical purification on silica gel
(pentane/diethyl ether = 10:1) afforded 9d (2.22 g, 78%) as a pale brown solid.
Mp. : 73.9-75.2 °C. 1H-NMR (CDCl3, 300 MHz): δ = 7.76 (d, J = 8.26 Hz, 1H), 7.74 (d, J = 1.65 Hz, 1H), 7.62 (dd,
J = 8.26 Hz, J = 1.65 Hz, 1H), 0.27 (s, 9H). 13C-NMR (CDCl3, 75 MHz): δ = 142.0, 135.3, 131.3, 127.0, 119.3, 117.1, 110.8, 110.7, 87.3,
-0.3.
IR (Diamond ATR, neat): ν~ = 3080 (w), 2927 (vw), 2898 (vw), 2229 (m), 2101 (m), 1584 (w),
1539 (w), 1454 (m), 1381 (m), 1375 (m), 1250 (s), 1190 (m), 1109 (w), 1025 (m), 896 (w), 844 (vs),
824 (s), 819 (vs), 758 (s), 702 (m), 692 (w), 674 (w).
MS (EI, 70 eV): m/z = 311 (10) [M+], 296 (28), 83 (100), 47 (11).
HR-MS: (C12H12NBrSSi) calculated: 308.9643 found: 308.9641.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
107
tert-Butyl 3-bromo-4-(((trimethylsilyl)ethynyl)thio)benzoate (9e):
The title compound was prepared according to TP11 from ethinyltrimethylsilane (2.06 g, 21.0
mmol, 1.40 equiv) i-PrMgCl· LiCl (13.5 mL, 1.34 M, 18.1 mmol, 1.20 equiv) and sulfonothioate
42e (6.44 g, 15.0 mmol, 1.00 equiv). Flash column chromatographical purification on silica gel
(pentane/diethyl ether = 20:1, 4% TEA) afforded 9e (4.98 g, 86%) as a colorless oil. 1H-NMR (CDCl3, 300 MHz): δ = 8.06 (d, J = 1.72 Hz, 1H), 7.94 (dd, J = 8.39 Hz, J = 1.72 Hz,
1H), 7.70 (d, J = 8.39 Hz, 1H), 1.58 (s, 9H), 0.27 (s, 9H). 13C-NMR (CDCl3, 75 MHz): δ = 164.0, 139.9, 133.4, 131.3, 128.8, 126.4, 118.9, 109.4, 93.7,
81.8, 28.1, -0.2.
IR (Diamond ATR, neat): ν~ = 2961 (w), 2095 (w), 1715 (s), 1586 (w), 1553 (w), 1472 (vw),
1457 (w), 1392 (w), 1377 (w), 1367 (m), 1295 (s), 1276 (m), 1246 (s), 1239 (s), 1163 (s), 1121 (s),
1107 (m), 1053 (vw), 1023 (m), 873 (vs), 840 (vs), 757 (vs), 735 (m), 725 (w), 700 (w), 665 (w).
MS (EI, 70 eV): m/z = 386 (15) [M+], 328 (14), 315 (100), 311 (14), 57 (10).
HR-MS: (C16H21O2BrSSi) calculated: 384.0215 found: 384.0209.
((Benzo[b]thiophen-3-ylthio)ethynyl)trimethylsilane (9f):
S
S TMS
The title compound was prepared according to TP11 from ethinyltrimethylsilane (2.00 g, 20.4
mmol, 1.30 equiv) i-PrMgCl· LiCl (13.4 mL, 1.29 M, 17.2 mmol, 1.10 equiv) and sulfonothioate
42f (4.80 g, 15.7 mmol, 1.00 equiv). Flash column chromatographical purification on silica gel
(pentane) afforded 9f (3.48 g, 85%) as a colorless oil. 1H-NMR (CDCl3, 300 MHz): δ = 7.93-7.84 (m, 2H), 7.55 (s, 1H), 7.49-7.37 (m, 2H), 0.21 (s,
9H). 13C-NMR (CDCl3, 75 MHz): δ = 140.0, 137.1, 125.5, 125.0, 124.5, 123.0, 122.1, 121.3, 103.5,
90.1, -0.2.
IR (Diamond ATR, neat): ν~ = 3097 (vw), 3059 (vw), 2957 (w), 2896 (vw), 2096 (m), 1454 (w),
1421 (m), 1315 (w), 1248 (s), 1148 (vw), 1062 (w), 1019 (w), 950 (vw), 872 (vs), 838 (vs), 829 (vs),
782 (w), 750 (vs), 725 (s), 702 (m).
MS (EI, 70 eV): m/z = 262 (100) [M+], 247 (62), 213 (17), 207 (27), 171 (52), 89 (19), 73 (56).
HR-MS: (C13H14S2Si) calculated: 262.0306 found: 262.0302.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
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((3-((2-Bromo-5-methoxyphenyl)thio)prop-2-yn-1-yl)oxy)triisopropylsilane (43a):
The title compound was prepared according to TP11 from triisopropyl(prop-2-yn-1-yloxy)silane
(4.67 g, 22.0 mmol, 1.10 equiv), i-PrMgCl· LiCl (16.3 mL, 1.29 M, 21.0 mmol, 1.05 equiv) and
sulfonothioate 42a (7.19 g, 20.0 mmol, 1.00 equiv). Flash column chromatographical purification
on silica gel (pentane/diethyl ether = 20:1) afforded 43a (6.96 g, 81%) as a colorless oil. 1H-NMR (CDCl3, 300 MHz): δ = 7.34 (d, J = 8.80 Hz, 1H), 7.27 (d, J = 2.93 Hz, 1H), 6.62 (dd,
J = 8.80 Hz, J = 2.93 Hz, 1H), 4.64 (s, 2H), 3.80 (s, 3H), 1.10-0.99 (m, 21H). 13C-NMR (CDCl3, 75 MHz): δ = 159.6, 135.4, 133.2, 116.7, 113.6, 112.7, 109.9, 100.4, 55.5,
52.9, 17.9, 12.0.
IR (Diamond ATR, neat): ν~ = 2940 (m), 2889 (w), 2864 (m), 1581 (m), 1567 (m), 1461 (s),
1432 (m), 1383 (w), 1365 (m), 1291 (m), 1261 (m), 1235 (m), 1226 (m), 1182 (w), 1096 (vs), 1070
(m), 1038 (s), 1012 (s), 995 (m), 919 (w), 881 (s), 867 (m), 841 (m), 793 (m), 683 (s), 664 (w).
MS (EI, 70 eV): m/z = 249 (37) [M+], 387 (59), 370 (36), 360 (100), 345 (71), 327 (22), 263 (32),
233 (19), 75 (18).
HR-MS: (C19H29O2BrSSi) calculated: 428.0841 found: 428.0833.
((3-((2-Bromo-4-chlorophenyl)thio)prop-2-yn-1-yl)oxy)triisopropylsilane (43b):
The title compound was prepared according to TP11 from triisopropyl(prop-2-yn-1-yloxy)silane
(3.51 g, 16.5 mmol, 1.00 equiv), i-PrMgCl· LiCl (12.8 mL, 1.29 M, 16.5 mmol, 1.00 equiv) and
sulfonothioate 42c (6.10 g, 16.5 mmol, 1.00 equiv). Flash column chromatographical purification
on silica gel (pentane) afforded 43b (6.31 g, 88%) as a colorless oil. 1H-NMR (CDCl3, 300 MHz): δ = 7.63 (d, J = 8.58 Hz, 1H), 7.50 (d, J = 2.29 Hz, 1H), 7.30 (dd,
J = 8.58 Hz, J = 2.29 Hz, 1H), 4.65 (s, 2H), 3.80 (s, 3H), 1.14-1.06 (m, 18H). 13C-NMR (CDCl3, 75 MHz): δ = 133.4, 132.4, 132.2, 128.3, 127.9, 119.6, 100.6, 82.5, 52.9, 17.9,
12.0.
IR (Diamond ATR, neat): ν~ = 3309 (vw), 2941 (m), 2889 (m), 2864 (m), 1734 (vw), 1568 (w),
1558 (w), 1548 (w), 1462 (m), 1447 (s), 1419 (vw), 1383 (w), 1365 (m), 1260 (w), 1247 (w), 1143
(w), 1097 (vs), 1069 (m), 1033 (m), 1022 (s), 1014 (m), 995 (m), 919 (w), 881 (s), 866 (m), 853
(vw), 809 (m), 798 (m), 781 (s), 682 (s), 660 (m).
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
109
MS (EI, 70 eV): m/z = 432 (1) [M+], 364 (26), 345 (63), 335 (100), 312 (19), 287 (15), 217 (17),
167 (19), 75 (25).
HR-MS: (C18H26OBrClSSi) calculated: 432.0346 found: 432.0331.
tert-Butyl 3-bromo-4-((3-((triisopropylsilyl)oxy)prop-1-yn-1-yl)thio)-benzoate (43c):
The title compound was prepared according to TP11 from triisopropyl(prop-2-yn-1-yloxy)silane
(2.1251 g, 10.0 mmol, 1.00 equiv), i-PrMgCl· LiCl (8.14 mL, 1.29 M, 10.5 mmol, 1.05 equiv) and
sulfonothioate 42e (4.72 g, 11.0 mmol, 1.10 equiv). Flash column chromatographical purification
on silica gel (pentane/diethyl ether = 20:1) afforded 43c (3.95 g, 79%) as a colorless oil. 1H-NMR (CDCl3, 300 MHz): δ = 8.06 (d, J = 1.53 Hz, 1H), 7.92 (dd, J = 8.39 Hz, J = 1.53 Hz,
1H), 7.74 (d, J = 8.39 Hz, 1H), 4.65 (s, 2H), 1.58 (s, 9H), 1.14-1.03 (m, 21H). 13C-NMR (CDCl3, 75 MHz): δ = 164.0, 140.3, 133.4, 131.2, 128.7, 126.4, 118.6, 101.0, 81.8,
52.9, 28.1, 17.9, 12.0, 12.0.
IR (Diamond ATR, neat): ν~ = 3001 (vw), 2956 (m), 2942 (m), 2903 (w), 2891 (w), 2865 (m),
1755 (vw), 1749 (vw), 1715 (s), 1586 (m), 1553 (w), 1458 (m), 1418 (vw), 1392 (w), 1368 (s), 1295
(vs), 1278 (m), 1257 (m), 1245 (s), 1240 (m), 1217 (w), 1163 (s), 1120 (s), 1104 (vs), 1070 (m),
1033 (m), 1023 (s), 996 (m), 919 (w), 900 (w), 881 (s), 848 (m), 821 (w), 771 (m), 760 (s), 737 (w),
683 (m).
MS (EI, 70 eV): m/z = 498 (1) [M+], 401 (98), 371 (67), 359 (100), 329 (13), 299 (11), 225 (14),
75 (29), 57 (44).
HR-MS: (C23H35O3BrSSi) calculated: 498.1260 found: 498.1252.
((3-(Benzo[b]thiophen-3-ylthio)prop-2-yn-1-yl)oxy)triisopropylsilane (43d):
The title compound was prepared according to TP11 from triisopropyl(prop-2-yn-1-yloxy)silane
(4.73 g, 22.3 mmol, 1.00 equiv), i-PrMgCl· LiCl (18.3 mL, 1.34 M, 24.5 mmol, 1.10 equiv) and
sulfonothioate 42f (7.27 g, 23.7 mmol, 1.05 equiv). Flash column chromatographical purification
on silica gel (pentane) afforded 43d (6.02 g, 72%) as a pale yellow oil. 1H-NMR (CDCl3, 300 MHz): δ = 7.96-7.83 (m, 2H), 7.59 (s, 1H), 7.46-7.48 (m, 2H), 4.50 (s,
2H), 1.11-1.02 (m, 21H).
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
110
13C-NMR (CDCl3, 75 MHz): δ = 139.9, 137.4, 126.8, 125.0, 124.6, 122.9, 122.4, 121.6, 94.6,
71.8, 52.8, 17.9, 12.0.
IR (Diamond ATR, neat): ν~ = 2940 (m), 2889 (m), 2863 (m), 1461 (m), 1456 (m), 1422 (m),
1382 (w), 1365 (m), 1317 (w), 1256 (m), 1147 (w), 1094 (vs), 1069 (s), 1032 (m), 1019 (m), 1013
(m), 995 (m), 959 (w), 950 (w), 918 (w), 881 (s), 828 (m), 778 (m), 775 (m), 752 (vs), 725 (s), 706
(w), 682 (s), 660 (w).
MS (EI, 70 eV): m/z = 376 (4) [M+], 333 (100), 159 (14), 124 (16), 115 (16), 75 (13), 59 (11).
HR-MS: (C20H28OS2Si) calculated: 376.1351 found: 376.1340.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
111
Cyclization of TMS-protected Alkynyl(aryl)thioethers
(6-Methoxy-3-(trimethylsilyl)benzo[b]thiophen-2-yl)(thiophen-2-yl)methanone (12a):
The title compound was prepared from the alkynyl(aryl)thioether 9a (946 mg, 3.00 mmol). A
Br/Mg-exchange was performed according to TP6 with i-PrMgCl· LiCl (2.44 mL, 1.29 M, 3.15
mmol, 1.05 equiv) at 25 °C within 4 h, followed by a CuCN· 2 LiCl (0.90 mL, 30 mol%)
mediated cyclization according to TP12 at 25 °C in 24 h. An acylation reaction was performed
according to TP4 using thiophene 2-carbonyl chloride (396 mg, 2.70 mmol) at -20 °C within 2 h.
Flash column chromatographical purification on silica gel (pentane/diethyl ether = 8:1) afforded
12a (676 mg, 72%) as a yellow solid.
Mp. : 106.1-107.8 °C. 1H-NMR (CDCl3, 300 MHz): δ = 7.97 (d, J = 8.85 Hz, 1H), 7.79 (dd, J = 3.73 Hz, J = 1.24 Hz,
1H), 7.74 (dd, J = 4.84 Hz, J = 1.24 Hz, 1H), 7.34 (d, J = 2.49 Hz, 1H), 7.14 (dd, J = 4.84 Hz, J =
3.73 Hz, 1H), 7.05 (dd, J = 8.85 Hz, J = 2.49 Hz, 1H), 3.89 (s, 3H), 0.36 (s, 9H). 13C-NMR (CDCl3, 75 MHz): δ = 183.5, 158.2, 145.2, 143.4, 143.3, 141.0, 138.2, 135.5, 135.1,
128.1, 127.0, 115.0, 104.1, 55.6, 0.9.
IR (Diamond ATR, neat): ν~ = 2951 (vw), 1627 (m), 1600 (m), 1541 (w), 1510 (m), 1487 (m),
1472 (w), 1465 (w), 1459 (w), 1446 (w), 1436 (w), 1419 (vw), 1406 (m), 1383 (w), 1350 (w), 1313
(vw), 1283 (m), 1262 (m), 1248 (s), 1226 (m), 1218 (m), 1178 (w), 1092 (m), 1074 (w), 1057 (m),
1043 (m), 1028 (m), 932 (m), 878 (m), 865 (m), 845 (vs), 830 (s), 808 (s), 755 (m), 731 (s), 709 (w),
704 (w), 693 (w), 671 (w).
MS (EI, 70 eV): m/z = 346 (19) [M+], 332 (100), 316 (39), 288 (67), 165 (20), 111 (21), 59 (13).
HR-MS: (C17H18O2S2Si) calculated: 346.0517 found: 346.0512.
(4-Chlorophenyl)(6-methoxy-3-(trimethylsilyl)benzo[b]thiophen-2-yl)methanone (12b):
The title compound was prepared from the alkynyl(aryl)thioether 9a (1.89 g, 6.00 mmol). A
Br/Mg-exchange was performed according to TP6 with i-PrMgCl· LiCl (4.88 mL, 1.29 M, 6.30
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
112
mmol, 1.05 equiv) at 25 °C within 4 h, followed by a CuCN· 2 LiCl (1.80 mL, 30 mol%)
mediated cyclization according to TP12 at 25 °C in 24 h. An acylation reaction was performed
according to TP4 using 4-chlorobenzoyl chloride (945 mg, 5.40 mmol) at -20 °C within 2 h.
Flash column chromatographical purification on silica gel (pentane/diethyl ether = 10:1) afforded
12b (1.62 g, 80%) as a pale yellow powder.
Mp. : 91.8-93.4 °C. 1H-NMR (CDCl3, 600 MHz): δ = 7.98 (d, J = 9.17 Hz, 1H), 7.89 (d, J = 8.80 Hz, 2H), 7.45 (d, J
= 8.80 Hz, 2H), 7.32 (d, J = 2.57 Hz, 1H), 7.05 (dd, J = 9.17 Hz, J = 2.57 Hz, 1H), 3.88 (s, 3H),
0.34 (s, 9H). 13C-NMR (CDCl3, 150 MHz): δ = 190.7, 158.3, 143.7, 143.6, 141.9, 139.8, 138.3, 136.9, 131.5,
128.7, 127.1, 115.1, 104.0, 55.6, 1.0.
IR (Diamond ATR, neat): ν~ = 2952 (w), 1644 (m), 1596 (s), 1540 (w), 1476 (s), 1439 (m),
1400 (m), 1394 (m), 1325 (w), 1285 (w), 1243 (s), 1222 (s), 1186 (m), 1173 (m), 1135 (m), 1111
(m), 1101 (m), 1085 (m), 1056 (m), 1026 (m), 1013 (m), 956 (m), 949 (m), 934 (w), 906 (m), 876
(s), 832 (vs), 811 (s), 773 (w), 757 (s), 741 (m), 716 (w), 707 (w), 698 (w), 679 (m).
MS (EI, 70 eV): m/z = 374 (6) [M+], 359 (100), 344 (12), 316 (23), 179 (5), 158 (5).
HR-MS: (C19H19O2SSi) calculated: 374.0564 found: 374.0556.
(4-Chlorophenyl)(6-((triisopropylsilyl)oxy)-3-(trimethylsilyl)benzo[b]thio-phen-2-
yl)methanone (12c):
The title compound was prepared from the alkynyl(aryl)thioether 9b (1.14 g, 2.50 mmol). A
Br/Mg-exchange was performed according to TP6 with i-PrMgCl· LiCl (2.05 mL, 1.29 M, 2.63
mmol, 1.05 equiv) at 25 °C within 6 h, followed by a CuCN· 2 LiCl (0.75 mL, 30 mol%)
mediated cyclization according to TP12 at 25 °C in 24 h. An acylation reaction was performed
according to TP4 using 4-chlorobenzoyl chloride (394 mg, 2.25 mmol) at -20 °C within 4 h.
Flash column chromatographical purification on silica gel (pentane/diethyl ether = 20:1) afforded
12c (969 mg, 83%) as a colorless oil. 1H-NMR (CDCl3, 300 MHz): δ = 7.94 (d, J = 8.97 Hz, 1H), 7.90 (d, J = 8.77 Hz, 2H), 7.45 (d, J
= 8.77 Hz, 2H), 7.33 (d, J = 2.29 Hz, 1H), 7.01 (dd, J = 8.97 Hz, J = 2.29 Hz, 1H), 1.38-1.25 (m,
3H), 1.14-1.12 (m, 18H), 0.35 (s, 9H).
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
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13C-NMR (CDCl3, 75 MHz): δ = 190.7, 154.8, 144.0, 143.4, 141.9, 139.8, 138.6, 136.9, 131.5,
128.7, 127.0, 119.0, 111.5, 17.9, 12.7, 1.0.
IR (Diamond ATR, neat): ν~ = 2943 (m), 2892 (w), 2865 (m), 1650 (m), 1593 (s), 1570 (w),
1536 (w), 1464 (s), 1398 (w), 1389 (w), 1368 (w), 1308 (w), 1270 (s), 1244 (s), 1216 (s), 1171 (m),
1135 (w), 1102 (m), 1088 (m), 1051 (w), 1014 (m), 996 (w), 937 (vs), 901 (m), 881 (m), 837 (vs),
814 (m), 786 (m), 753 (s), 739 (m), 685 (m), 666 (m).
MS (EI, 70 eV): m/z = 516 (13) [M+], 501 (100), 473 (20), 445 (12), 417 (13), 139 (24), 73 (55).
HR-MS: (C27H37O2ClSSi2) calculated: 516.1741 found: 516.1730.
Furan-2-yl(6-((triisopropylsilyl)oxy)-3-(trimethylsilyl)benzo[b]thiophen-2-yl)methanone
(12d):
The title compound was prepared from the alkynyl(aryl)thioether 9b (1.14 g, 2.50 mmol). A
Br/Mg-exchange was performed according to TP6 with i-PrMgCl· LiCl (2.05 mL, 1.29 M, 2.63
mmol, 1.05 equiv) at 25 °C within 6 h, followed by a CuCN· 2 LiCl (0.75 mL, 30 mol%)
mediated cyclization according to TP12 at 25 °C in 24 h. An acylation reaction was performed
according to TP4 using furan 2-carbonyl chloride (294 mg, 2.25 mmol) at -20 °C within 3 h.
Flash column chromatographical purification on silica gel (pentane/diethyl ether = 10:1) afforded
12d (927 mg, 87%) as a colorless oil. 1H-NMR (CDCl3, 300 MHz): δ = 7.96 (d, J = 8.58 Hz, 1H), 7.70 (dd, J = 1.72 Hz, J = 0.76 Hz,
1H), 7.33 (dd, J = 3.62 Hz, J = 0.76 Hz, 1H), 7.34 (d, J = 2.29 Hz, 1H), 6.99 (dd, J = 8.58 Hz, J =
2.29 Hz, 1H), 6.59 (dd, J = 3.62 Hz, J = 1.72 Hz, 1H), 1.36-1.23 (m, 3H), 1.16-1.08 (m, 18H),
0.38 (s, 9H). 13C-NMR (CDCl3, 75 MHz): δ = 177.6, 154.9, 152.8, 147.4, 143.6, 143.0, 142.7, 138.5, 127.2,
121.0, 119.0, 112.4, 111.5, 17.9, 12.7, 1.1.
IR (Diamond ATR, neat): ν~ = 2944 (m), 2892 (w), 2865 (m), 1733 (w), 1717 (w), 1683 (vw),
1636 (m), 1594 (s), 1564 (m), 1535 (w), 1505 (vw), 1462 (s), 1387 (m), 1368 (w), 1309 (w), 1261
(s), 1247 (s), 1218 (s), 1160 (m), 1136 (m), 1109 (m), 1083 (w), 1076 (w), 1055 (w), 1013 (m), 996
(w), 946 (s), 916 (s), 877 (s), 838 (vs), 813 (s), 751 (s), 685 (m), 668 (m).
MS (EI, 70 eV): m/z = 472 (9) [M+], 457 (100), 429 (16), 401 (10), 179 (24), 73 (36).
HR-MS: (C25H36O3SSi2) calculated: 472.1924 found: 472.1919.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
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(5-Chloro-3-(trimethylsilyl)benzo[b]thiophen-2-yl)(furan-2-yl)methanone (12e):
The title compound was prepared from the alkynyl(aryl)thioether 9c (959 mg, 3.00 mmol). A
Br/Mg-exchange was performed according to TP6 with i-PrMgCl· LiCl (2.35 mL, 1.34 M, 3.15
mmol, 1.05 equiv) at 25 °C within 1 h, followed by a CuCN· 2 LiCl (0.90 mL, 30 mol%)
mediated cyclization according to TP12 at 25 °C in 26 h. An acylation reaction was performed
according to TP4 using furan 2-carbonyl chloride (353 mg, 2.70 mmol) at -30 °C within 2 h.
Flash column chromatographical purification on silica gel (pentane/diethyl ether = 6:1) afforded
12e (704 mg, 78%) as a colorless oil. 1H-NMR (CDCl3, 600 MHz): δ = 8.05 (d, J = 1.92 Hz, 1H), 7.82 (d, J = 8.54 Hz, 1H), 7.73 (dd,
J = 1.74 Hz, J = 0.87 Hz, 1H), 7.39 (dd, J = 8.54 Hz, J = 1.92 Hz, 1H), 7.29 (dd, J = 3.57 Hz, J =
0.87 Hz, 1H), 6.60 (dd, J = 3.57 Hz, J = 1.74 Hz, 1H), 0.37 (s, 9H). 13C-NMR (CDCl3, 150 MHz): δ = 177.9, 152.6, 148.0, 146.8, 145.1, 141.1, 139.6, 130.8, 126.2,
125.8, 123.4, 121.7, 112.7, 0.9.
IR (Diamond ATR, neat): ν~ = 2952 (w), 1640 (s), 1605 (w), 1579 (w), 1557 (m), 1536 (w),
1476 (m), 1460 (s), 1425 (m), 1400 (w), 1387 (m), 1312 (w), 1287 (m), 1267 (m), 1249 (s), 1227
(w), 1165 (m), 1150 (w), 1123 (m), 1081 (m), 1064 (m), 1017 (m), 963 (s), 938 (m), 925 (w), 889
(m), 881 (m), 865 (s), 851 (s), 836 (s), 826 (vs), 796 (s), 775 (vs), 759 (s), 738 (m), 731 (m), 714
(m), 692 (m).
MS (EI, 70 eV): m/z = 334 (1) [M+], 319 (100), 152 (8), 71 (5), 57 (7), 43 (10).
HR-MS: (C16H15O2ClSSi) calculated: 334.0251 found: 334.0255.
(5-Chloro-3-(trimethylsilyl)benzo[b]thiophen-2-yl)(6-chloropyridin-3-yl)methanone (12f):
The title compound was prepared from the alkynyl(aryl)thioether 9c (959 mg, 3.00 mmol). A
Br/Mg-exchange was performed according to TP6 with i-PrMgCl· LiCl (2.35 mL, 1.34 M, 3.15
mmol, 1.05 equiv) at 25 °C within 1 h, followed by a CuCN· 2 LiCl (0.90 mL, 30 mol%)
mediated cyclization according to TP12 at 25 °C in 26 h. An acylation reaction was performed
according to TP4 using 6-chloronicotinoyl chloride (475 mg, 2.70 mmol) at -30 °C within 4 h.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
115
Flash column chromatographical purification on silica gel (pentane/diethyl ether = 10:1) afforded
12f (925 mg, 90%) as a yellow viscous oil. 1H-NMR (CDCl3, 400 MHz): δ = 8.88 (dd, J = 2.44 Hz, J = 0.68 Hz, 1H), 8.19 (dd, J = 8.29
Hz, J = 2.44 Hz, 1H), 8.06 (dd, J = 2.05 Hz, J = 0.49 Hz, 1H), 7.82 (dd, J = 8.58 Hz, J = 0.49 Hz,
1H), 7.48 (dd, J = 8.29 Hz, J = 0.68 Hz, 1H), 7.42 (dd, J = 8.58 Hz, J = 2.05 Hz, 1H), 0.37 (s,
9H). 13C-NMR (CDCl3, 100 MHz): δ = 189.2, 156.2, 151.5, 146.6, 145.3, 142.1, 139.7, 139.4, 132.3,
131.2, 126.6, 125.9, 124.5, 123.5, 0.9.
IR (Diamond ATR, neat): ν~ = 2950 (w); 2896 (vw); 1652 (m); 1576 (s); 1555 (m); 1537 (w);
1455 (m); 1403 (m); 1360 (m); 1310 (vw); 1287 (m); 1249 (s); 1239 (s); 1119 (m); 1099 (s); 1080
(s); 1063 (m); 1020 (w); 964 (s); 907 (m); 857 (s); 836 (vs); 798 (s); 754 (s); 728 (m); 719 (m); 707
(w); 693 (w); 690 (w).
MS (EI, 70 eV): m/z = 379 (2) [M+], 364 (100), 176 (5), 140 (5), 74 (8), 59 (11), 45 (8).
HR-MS: (C17H15ONCl2SSi) calculated: 379.0021 found: 379.0012.
Ethyl 2-((5-chloro-3-(trimethylsilyl)benzo[b]thiophen-2-yl)methyl)acrylate (12g):
The title compound was prepared from the alkynyl(aryl)thioether 9c (959 mg, 3.00 mmol). A
Br/Mg-exchange was performed according to TP6 with i-PrMgCl· LiCl (2.35 mL, 1.34 M, 3.15
mmol, 1.05 equiv) at 25 °C within 1 h, followed by a CuCN· 2 LiCl (0.90 mL, 30 mol%)
mediated cyclization according to TP12 at 25 °C in 26 h. An allylation reaction was performed
according to TP4 using ethyl 2-(bromomethyl)acrylate (521 mg, 2.70 mmol) at 0 °C within 1 h.
Flash column chromatographical purification on silica gel (pentane/diethyl ether = 10:1) afforded
12g (735 mg, 90%) as a colorless oil. 1H-NMR (CDCl3, 400 MHz): δ = 7.82 (dd, J = 1.95Hz, J = 0.39 Hz, 1H), 7.69 (dd, J = 8.48
Hz, J = 0.39 Hz, 1H), 7.23 (dd, J = 8.48 Hz, J = 1.95 Hz, 1H), 6.33(d, J = 1.17 Hz, 1H), 5.43 (d, J
= 1.17 Hz, 1H), 4.23 (q, J = 7.21 Hz, 2H), 3.98 (s, 2H), 1.29 (t, J = 7.21 Hz, 3H), 0.42 (s, 9H). 13C-NMR (CDCl3, 100 MHz): δ = 166.3, 151.0, 146.4, 139.7, 138.6, 131.9, 129.9, 126.7, 123.9,
123.7, 122.8, 61.0, 33.3, 14.2, 0.9.
IR (Diamond ATR, neat): ν~ = 2956 (w), 2953 (w), 2903 (vw), 2898 (vw), 1713 (s), 1683 (vw),
1652 (vw), 1633 (w), 1581 (w), 1538 (w), 1504 (w), 1476 (w), 1463 (w), 1455 (w), 1432 (m), 1401
(m), 1367 (w), 1327 (w), 1304 (w), 1278 (m), 1267 (m), 1250 (s), 1210 (m), 1172 (m), 1141 (s),
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
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1121 (m), 1095 (w), 1080 (s), 1063 (w), 1025 (m), 948 (m), 849 (s), 836 (vs), 797 (s), 778 (m), 761
(s), 729 (m), 713 (m), 688 (m), 657 (w).
MS (EI, 70 eV): m/z = 352 (10) [M+], 337 (16), 323 (10), 208 (9), 171 (9), 103 (10), 74 (62), 59
(100), 45 (64).
HR-MS: (C17H21O2ClSSi) calculated: 352.0720 found: 352.0710.
(5-Chloro-3-(trimethylsilyl)benzo[b]thiophen-2-yl)(thiophen-2-yl)methanone (12h):
The title compound was prepared from the alkynyl(aryl)thioether 9c (959 mg, 3.00 mmol). A
Br/Mg-exchange was performed according to TP6 with i-PrMgCl· LiCl (2.35 mL, 1.34 M, 3.15
mmol, 1.05 equiv) at 25 °C within 1 h, followed by a CuCN· 2 LiCl (0.90 mL, 30 mol%)
mediated cyclization according to TP12 at 25 °C in 26 h. An acylation reaction was performed
according to TP4 using thiophene 2-carbonyl chloride (396 mg, 2.70 mmol) at -30 °C within 2 h.
Flash column chromatographical purification on silica gel (pentane/diethyl ether = 10:1) afforded
12h (818 mg, 86%) as a yellow solid.
Mp. : 125.0-128.2 °C. 1H-NMR (CDCl3, 400 MHz): δ = 8.01 (dd, J = 1.95 Hz, J = 0.39 Hz, 1H), 7.82 (dd, J = 8.58
Hz, J = 0.39 Hz, 1H), 7.78 (dd, J = 4.87 Hz, J = 1.17 Hz, 1H), 7.72 (dd, J = 3.90 Hz, J = 1.17 Hz,
1H), 7.39 (dd, J = 8.58 Hz, J = 1.95 Hz, 1H), 7.15 (dd, J = 4.87 Hz, J = 3.90 Hz, 1H), 0.35 (s,
9H). 13C-NMR (CDCl3, 100 MHz): δ = 183.8, 147.7, 145.1, 144.8, 139.3, 139.2, 136.0, 135.9, 130.8,
128.3, 125.9, 125.5, 123.3, 0.7.
IR (Diamond ATR, neat): ν~ = 3089 (vw), 2948 (w), 1631 (s), 1578 (w), 1513 (m), 1475 (m),
1421 (w), 1408 (s), 1351 (m), 1263 (s), 1248 (s), 1230 (s), 1204 (w), 1103 (m), 1081 (m), 1059 (m),
1035 (m), 1021 (w), 949 (s), 937 (m), 889 (m), 872 (m), 848 (s), 837 (vs), 816 (s), 801 (s), 795 (vs),
759 (m), 750 (m), 743 (m), 735 (s), 730 (vs), 698 (m), 688 (m).
MS (EI, 70 eV): m/z = 350 (2) [M+], 337 (100), 240 (6), 160 (16), 111 (22), 74 (36), 59 (59), 45
(38).
HR-MS: (C16H15OClS2Si) calculated: 350.0022 found: 350.0018.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
117
(4-Bromophenyl)(5-chloro-3-(trimethylsilyl)benzo[b]thiophen-2-yl)methanone (12i):
The title compound was prepared from the alkynyl(aryl)thioether 9c (959 mg, 3.00 mmol). A
Br/Mg-exchange was performed according to TP6 with i-PrMgCl· LiCl (2.35 mL, 1.34 M, 3.15
mmol, 1.05 equiv) at 25 °C within 1 h, followed by a CuCN· 2 LiCl (0.90 mL, 30 mol%)
mediated cyclization according to TP12 at 25 °C in 26 h. An acylation reaction was performed
according to TP4 using 4-bromobenzoyl chloride (593 mg, 2.79 mmol) at -30 °C within 2 h.
Flash column chromatographical purification on silica gel (pentane/diethyl ether = 10:1) afforded
12i (1.10 g, 96%) as a pale yellow solid.
Mp. : 96.1-97.9 °C. 1H-NMR (CDCl3, 400 MHz): δ = 8.02 (dd, J = 2.05 Hz, J = 0.49 Hz, 1H), 7.80 (dd, J = 8.67
Hz, J = 0.49 Hz, 1H), 7.79 (d, J = 8.77 Hz, 2H), 7.63 (d, J = 8.77 Hz, 2H), 7.39 (dd, J = 8.67 Hz,
J = 2.05 Hz, 1H), 0.33 (s, 9H). 13C-NMR (CDCl3, 100 MHz): δ = 191.2, 147.8, 145.2, 139.9, 139.4, 136.5, 131.9, 131.6, 130.9,
129.3, 126.1, 125.6, 123.3, 0.8.
IR (Diamond ATR, neat): ν~ = 3087 (vw), 2942 (vw), 2363 (vw), 1646 (s), 1585 (m), 1564 (w),
1532 (w), 1484 (w), 1466 (m), 1436 (w), 1405 (m), 1396 (m), 1312 (w), 1306 (w), 1258 (s), 1249
(s), 1243 (s), 1232 (s), 1177 (m), 1147 (w), 1117 (m), 1110 (w), 1077 (m), 1067 (m), 1013 (w), 967
(s), 953 (m), 935 (w), 905 (m), 862 (s), 853 (s), 846 (s), 836 (vs), 792 (s), 763 (m), 750 (s), 725 (m),
705 (w), 697 (w), 685 (m).
MS (EI, 70 eV): m/z = 421 (2) [M+], 409 (100), 197 (11), 183 (6), 81 (5), 74 (9), 59 (12).
HR-MS: (C18H16OClBrSSi) calculated: 421.9563 found: 421.9540.
2-(Furan-2-carbonyl)-3-(trimethylsilyl)benzo[b]thiophene-5-carbonitrile (12j):
The title compound was prepared from the alkynyl(aryl)thioether 9d (931 mg, 3.00 mmol). A
Br/Mg-exchange was performed according to TP6 with i-PrMgCl· LiCl (2.35 mL, 1.34 M, 3.15
mmol, 1.05 equiv) at 0 °C within 1 h, followed by a CuCN· 2 LiCl (0.90 mL, 30 mol%) mediated
cyclization according to TP12 at 25 °C in 24 h. An acylation reaction was performed according to
TP4 using furan 2-carbonyl chloride (353 mg, 2.70 mmol) at 0 °C within 1 h. Flash column
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
118
chromatographical purification on silica gel (pentane/diethyl ether = 3:1) afforded 12j (708 mg,
81%) as a white powder.
Mp. : 174.0-175.7 °C. 1H-NMR (CDCl3, 300 MHz): δ = 8.38 (dd, J = 1.43 Hz, J = 0.67 Hz, 1H), 8.00 (dd, J = 8.39
Hz, J = 0.76 Hz, 1H), 7.74 (dd, J = 1.62Hz, J = 0.76 Hz, 1H), 7.62 (dd, J = 8.39 Hz, J = 1.62 Hz,
1H), 7.29 (dd, J = 3.62 Hz, J = 0.67 Hz, 1H), 6.62 (dd, J = 3.62 Hz, J = 1.43 Hz, 1H), 0.37 (s,
9H). 13C-NMR (CDCl3, 75 MHz): δ = 177.5, 152.4, 148.2, 147.3, 145.5, 143.7, 141.4, 130.7, 127.3,
123.5, 121.9, 119.2, 112.9, 108.4, 0.8.
IR (Diamond ATR, neat): ν~ = 3132 (w), 2957 (vw), 2229 (w), 1645 (s), 1559 (w), 1494 (w),
1459 (m), 1454 (m), 1440 (w), 1408 (w), 1385 (m), 1365 (w), 1300 (m), 1256 (m), 1250 (m), 1231
(w), 1167 (w), 1158 (w), 1154 (w), 1119 (m), 1025 (m), 979 (m), 932 (w), 884 (m), 880 (m), 870 (s),
843 (vs), 816 (vs), 791 (s), 761 (m), 748 (m), 733 (w), 707 (w), 700 (w), 690 (w).
MS (EI, 70 eV): m/z = 325 (1) [M+], 311 (100), 280 (11), 164 (6), 148 (22),
HR-MS: (C17H15O2NSSi) calculated: 325.0593 found: 325.0591.
2-Allyl-3-(trimethylsilyl)benzo[b]thiophene-5-carbonitrile (12k):
The title compound was prepared from the alkynyl(aryl)thioether 9d (931 mg, 3.00 mmol). A
Br/Mg-exchange was performed according to TP6 with i-PrMgCl· LiCl (2.35 mL, 1.34 M, 3.15
mmol, 1.05 equiv) at 0 °C within 1 h, followed by a CuCN· 2 LiCl (0.90 mL, 30 mol%) mediated
cyclization according to TP12 at 25 °C in 24 h. An allylation reaction was performed according to
TP4 using allyl bromide (327 mg, 2.70 mmol) at 25 °C within 1 h. Flash column
chromatographical purification on silica gel (pentane/diethyl ether = 8:1) afforded 12k (611 mg,
83%) as a colorless oil. 1H-NMR (CDCl3, 300 MHz): δ = 8.14 (dd, J = 1.53 Hz, J = 0.57 Hz, 1H), 7.86 (dd, J = 8.30
Hz, J = 0.57 Hz, 1H), 7.46 (dd, J = 8.30 Hz, J = 1.53 Hz, 1H), 6.09-5.94 (m, 1H), 5.21-5.07 (m,
2H), 3.80-3.72 (m, 2H), 0.46 (s, 9H). 13C-NMR (CDCl3, 75 MHz): δ = 153.8, 145.1, 145.0, 135.9, 131.2, 128.4, 125.3, 122.8, 119.9,
117.4, 107.3, 35.4, 1.1.
IR (Diamond ATR, neat): ν~ = 2954 (w), 2225 (m), 1639 (w), 1592 (w), 1491 (w), 1486 (w),
1440 (m), 1406 (w), 1313 (w), 1252 (s), 1164 (w), 1158 (w), 1131 (w), 1120 (w), 1066 (w), 1044
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
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(w), 987 (w), 974 (w), 953 (w), 920 (w), 902 (w), 855 (s), 838 (vs), 811 (m), 762 (m), 734 (w), 715
(w), 693 (w), 690 (w).
MS (EI, 70 eV): m/z = 271 (66) [M+], 256 (100), 240 (20), 176 (10), 73 (13), 59 (15).
HR-MS: (C15H17NSSi) calculated: 271.0851 found: 271.0861.
2-Pivaloyl-3-(trimethylsilyl)benzo[b]thiophene-5-carbonitrile (12l):
S
TMS
COt-Bu
NC
The title compound was prepared from the alkynyl(aryl)thioether 9d (931 mg, 3.00 mmol). A
Br/Mg-exchange was performed according to TP6 with i-PrMgCl· LiCl (2.35 mL, 1.34 M, 3.15
mmol, 1.05 equiv) at 0 °C within 1 h, followed by a CuCN· 2 LiCl (0.90 mL, 30 mol%) mediated
cyclization according to TP12 at 25 °C in 24 h. An acylation reaction was performed according to
TP4 using pivaloyl chloride (326 mg, 2.70 mmol) at 25 °C within 1 h. Flash column
chromatographical purification on silica gel (pentane/diethyl ether = 8:1) afforded 12l (692 mg,
80%) as a white powder.
Mp. : 107.9-109.6 °C. 1H-NMR (CDCl3, 300 MHz): δ = 8.33 (dd, J = 1.43 Hz, J = 0.67 Hz, 1H), 7.95 (dd, J = 8.39
Hz, J = 0.67 Hz, 1H), 7.59 (dd, J = 8.39 Hz, J = 1.43 Hz, 1H), 1.37 (s, 9H), 0.39 (s, 9H). 13C-NMR (CDCl3, 75 MHz): δ = 206.0, 148.3, 144.6, 143.2, 139.8, 130.3, 127.1, 123.2, 119.3,
108.2, 44.5, 27.2, 1.1.
IR (Diamond ATR, neat): ν~ = 2966 (w), 2931 (w), 2903 (w), 2870 (vw), 2226 (m), 2116 (w),
1672 (m), 1651 (w), 1637 (w), 1580 (w), 1475 (m), 1461 (w), 1443 (w), 1430 (w), 1410 (w), 1394
(w), 1364 (m), 1259 (m), 1249 (m), 1245 (m), 1158 (w), 1126 (s), 1101 (m), 1073 (w), 1039 (w),
1026 (w), 1017 (w), 989 (m), 923 (w), 914 (w), 900 (w), 863 (s), 843 (s), 818 (vs), 787 (m), 761 (s),
756 (s), 734 (m), 715 (w), 697 (w), 686 (w).
MS (EI, 70 eV): m/z = 315 (1) [M+], 300 (72), 285 (24), 270 (16), 258 (100), 200 (5).
HR-MS: (C17H21ONSSi) calculated: 315.1113 found: 315.1101.
tert-Butyl 2-pivaloyl-3-(trimethylsilyl)benzo[b]thiophene-5-carboxylate (12m):
S
TMS
COt-Bu
t-BuO2C
The title compound was prepared from the alkynyl(aryl)thioether 9e (386 mg, 1.00 mmol). A
Br/Mg-exchange was performed according to TP6 with i-PrMgCl· LiCl (0.79 mL, 1.34 M, 1.05
mmol, 1.05 equiv) at -25 °C within 1 h. After adding CuCN· 2 LiCl (1.00 mL, 100 mol%) the
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
120
cyclization was achieved by a microwave reaction according to TP13 (50 °C, 100W, 1 h) An
acylation reaction was performed according to TP4 using pivaloyl chloride (109 mg, 0.90 mmol)
at 25 °C within 1 h. Flash column chromatographical purification on silica gel (pentane/diethyl
ether = 20:1) afforded 12m (356 mg, 91%) as a white solid.
Mp. : 113.9-115.6 °C. 1H-NMR (CDCl3, 300 MHz): δ = 8.76 (d, J = 1.38 Hz, 1H), 7.99 (dd, J = 8.29 Hz, J = 1.38 Hz,
1H), 7.87 (d, J = 8.29 Hz, 1H), 1.62 (s, 9H), 1.38 (s, 9H), 0.41 (s, 9H). 13C-NMR (CDCl3, 75 MHz): δ = 206.2, 165.8, 147.0, 144.5, 143.1, 140.8, 128.4, 127.8, 125.7,
121.7, 81.1, 44.5, 28.2, 27.3, 1.2.
IR (Diamond ATR, neat): ν~ = 2978 (w), 2961 (w), 1703 (s), 1668 (s), 1475 (w), 1466 (m), 1407
(w), 1368 (m), 1364 (m), 1308 (s), 1266 (w), 1251 (m), 1241 (m), 1228 (m), 1166 (s), 1139 (s),
1099 (vs), 1073 (w), 990 (s), 930 (m), 903 (w), 873 (s), 839 (vs), 825 (s), 819 (m), 757 (vs), 737 (w),
697 (w), 682 (w).
MS (EI, 70 eV): m/z = 390 (1) [M+], 375 (58), 333 (18), 319 (66), 304 (20), 277 (100).
HR-MS: (C21H30O3SSi) calculated: 390.1685 found: 390.1674.
tert-Butyl 2-(furan-2-carbonyl)-3-(trimethylsilyl)benzo[b]thiophene-5-carboxylate (12n):
The title compound was prepared from the alkynyl(aryl)thioether 9e (964 mg, 2.50 mmol). A
Br/Mg-exchange was performed according to TP6 with i-PrMgCl· LiCl (1.96 mL, 1.34 M, 2.63
mmol, 1.05 equiv) at -25 °C within 1 h. After adding CuCN· 2 LiCl (2.75 mL, 100 mol%) the
cyclization was achieved by a microwave reaction according to TP13 (50 °C, 100 W, 1 h) An
acylation reaction was performed according to TP4 using furan 2-carbonylchloride (294 mg, 2.25
mmol) at -25 °C within 4 h. Flash column chromatographical purification on silica gel
(pentane/diethyl ether = 6:1) afforded 12n (732 mg, 81%) as a white powder.
Mp. : 87.5-90.4 °C. 1H-NMR (CDCl3, 300 MHz): δ = 8.80 (d, J = 1.38 Hz, 1H), 8.03 (dd, J = 8.57 Hz, J = 1.94 Hz,
1H), 7.92 (d, J = 8.57 Hz, 1H), 7.73(d, J = 1.94 Hz, 1H), 7.30 (d, J = 3.59 Hz, 1H), 6.60 (dd, J =
3.59 Hz, J = 1.38 Hz, 1H), 1.63 (s, 9H), 0.40 (s, 9H). 13C-NMR (CDCl3, 75 MHz): δ = 177.9, 165.7, 152.6, 147.9, 145.9, 145.4, 143.7, 142.7, 128.6,
128.2, 126.0, 122.0, 121.7, 112.7, 81.2, 28.2, 0.9.
IR (Diamond ATR, neat): ν~ = 3116 (vw), 2975 (w), 1711 (s), 1670 (w), 1654 (w), 1632 (m),
1597 (w), 1567 (w), 1553 (w), 1457 (s), 1418 (m), 1388 (m), 1367 (m), 1309 (s), 1285 (s), 1252 (s),
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
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1240 (s), 1226 (m), 1166 (s), 1146 (s), 1121 (m), 1098 (s), 1082 (m), 1068 (m), 1038 (w), 1025 (m),
986 (m), 961 (w), 946 (w), 903 (w), 886 (m), 878 (m), 872 (s), 832 (vs), 771 (s), 759 (vs), 755 (vs),
738 (s), 713 (w), 697 (w), 690 (w), 686 (w), 680 (w).
MS (EI, 70 eV): m/z = 400 (2) [M+], 385 (27), 329 (100), 156 (5), 95 (6).
HR-MS: (C21H24O4SSi) calculated: 400.1165 found: 400.1146.
tert-Butyl 2-(2-(ethoxycarbonyl)allyl)-3-(trimethylsilyl)benzo[b]thiophene-5-carboxylate
(12o):
The title compound was prepared from the alkynyl(aryl)thioether 9e (964 mg, 2.50 mmol). A
Br/Mg-exchange was performed according to TP6 with i-PrMgCl· LiCl (1.96 mL, 1.34 M, 2.63
mmol, 1.05 equiv) at -25 °C within 1 h. After adding CuCN· 2 LiCl (2.75 mL, 100 mol%) the
cyclization was achieved by a microwave reaction according to TP13 (50 °C, 100 W, 1 h) An
allylation reaction was performed according to TP4 using ethyl 2-(bromomethyl)acrylate (434
mg, 2.25 mmol) at -40 °C within 1 h. Flash column chromatographical purification on silica gel
(pentane/diethyl ether = 9:1) afforded 12o (671 mg, 71%) as a colorless oil. 1H-NMR (CDCl3, 300 MHz): δ = 8.58 (d, J = 1.38 Hz, 1H), 7.87 (dd, J = 8.29 Hz, J = 1.38 Hz,
1H), 7.79 (d, J = 8.29 Hz, 1H), 6.33 (d, J = 1.11 Hz, 1H), 5.44 (d, J = 1.11 Hz, 1H), 4.23 (q, J =
7.00 Hz, 2H), 4.00 (s, 2H), 1.61 (s, 9H), 1.29 (q, J = 7.00 Hz, 3H), 0.45 (s, 9H). 13C-NMR (CDCl3, 75 MHz): δ = 166.3, 166.1, 150.0, 145.0, 144.8, 139.7, 133.0, 127.7, 126.7,
126.0, 123.8, 121.5, 80.8, 61.0, 33.3, 28.2, 14.2, 0.9.
IR (Diamond ATR, neat): ν~ = 2975 (w), 1708 (vs), 1633 (w), 1595 (w), 1547 (vw), 1505 (vw),
1477 (w), 1455 (w), 1442 (w), 1412 (w), 1392 (w), 1366 (m), 1319 (m), 1305 (m), 1294 (s), 1266
(m), 1250 (s), 1209 (m), 1161 (s), 1145 (s), 1124 (m), 1100 (s), 1063 (w), 1024 (m), 974 (m), 946
(m), 906 (w), 873 (m), 836 (vs), 759 (s), 712 (w), 689 (w).
MS (EI, 70 eV): m/z = 418 (46) [M+], 403 (83), 347 (50), 301 (62), 272 (75), 227 (64), 73 (100).
HR-MS: (C22H30O4SSi) calculated: 418.1634 found: 418.1629.
Benzo[b]thieno[2,3-d]thiophen-3-yltrimethylsilane (12p):
S
S
TMS
The title compound was prepared from the alkynyl(aryl)thioether 9f (788 mg, 3.00 mmol). After
metalation with TMPMgCl· LiCl (3.05 mL, 1.08 M, 3.30 mmol) according to TP1 at 25 °C in 2 h
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
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and addition of CuCN· 2 LiCl (0.90 mL, 30 mol%), the cyclization was carried out according to
TP13 (75 °C, 200 W, 3 h). Flash column chromatographical purification on silica gel (pentane)
afforded 12p (565 mg, 81%) as a pale green oil. 1H-NMR (CDCl3, 300 MHz): δ = 7.88-7.82 (m, 2H), 7.54 (s, 1H), 7.44-7.30 (m, 2H), 0.42 (s,
9H). 13C-NMR (CDCl3, 75 MHz): δ = 143.0, 142.8, 135.3, 134.3, 134.1, 132.5, 124.5, 124.2, 123.8,
121.2, -1.2.
IR (Diamond ATR, neat): ν~ = 2953 (w), 2894 (vw), 2092 (vw), 1473 (w), 1453 (w), 1433 (m),
1323 (w), 1318 (m), 1306 (w), 1291 (w), 1248 (s), 1163 (w), 1156 (w), 1131 (vw), 1068 (m), 1018
(w), 994 (m), 966 (m), 949 (vw), 899 (vw), 874 (w), 834 (vs), 816 (s), 752 (vs), 721 (s), 705 (m),
695 (m).
MS (EI, 70 eV): m/z = 262 (51) [M+], 247 (100), 123 (12), 97 (11), 73 (16).
HR-MS: (C13H14S2Si) calculated: 262.0306 found: 262.0304.
(4-Chlorophenyl)(3-(trimethylsilyl)benzo[b]thieno[2,3-d]thiophen-2-yl)methanone (12q):
The title compound was prepared from the alkynyl(aryl)thioether 9f (788 mg, 3.00 mmol). After
metalation with TMPMgCl· LiCl (3.05 mL, 1.08 M, 3.30 mmol) according to TP1 at 25 °C in 2 h
and addition of CuCN· 2 LiCl (0.90 mL, 30 mol%), the cyclization was carried out according to
TP13 (75 °C, 200 W, 3 h). An acylation reaction was performed according to TP4 using 4-
chlorobenzoyl chloride (473 mg, 2.70 mmol) at 0 °C within 1 h. Flash column chromatographical
purification on silica gel (pentane/diethyl ether = 30:1) afforded 12q (418 mg, 39%) as a colorless
oil. 1H-NMR (CDCl3, 300 MHz): δ = 7.89 (d, J = 8.62 Hz, 2H), 7.87-7.83 (m, 2H), 7.49 (d, J = 8.62
Hz, 2H), 7.43-7.39 (m, 2H), 0.50 (s, 9H). 13C-NMR (CDCl3, 75 MHz): δ = 187.9, 146.4, 145.8, 143.9, 143.1, 140.1, 139.0, 137.4, 131.2,
130.9, 128.6, 126.1, 125.0, 123.6, 121.8, 0.2.
IR (Diamond ATR, neat): ν~ = 2938 (w), 2861 (w), 2360 (w), 2339 (w), 1717 (w), 1623 (m),
1616 (m), 1593 (w), 1471 (w), 1464 (w), 1456 (w), 1446 (w), 1436 (w), 1415 (m), 1394 (w), 1387
(w), 1373 (m), 1365 (m), 1349 (m), 1319 (m), 1304 (m), 1280 (w), 1263 (m), 1217 (w), 1175 (w),
1088 (s), 1072 (m), 1069 (m), 1064 (m), 1020 (w), 1014 (m), 994 (m), 970 (w), 950 (m), 878 (m),
842 (m), 828 (m), 800 (s), 754 (vs), 727 (m), 679 (w).
MS (EI, 70 eV): m/z = 400 (3) [M+], 385 (100), 355 (5), 193 (8), 185 (6), 139 (3).
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
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HR-MS: (C20H17OClS2Si) calculated: 400.0179 found: 400.0170.
Ethyl 2-((3-(trimethylsilyl)benzo[b]thieno[2,3-d]thiophen-2-yl)methyl)acrylate (12r):
The title compound was prepared from the alkynyl(aryl)thioether 9f (788 mg, 3.00 mmol). After
metalation with TMPMgCl· LiCl (3.05 mL, 1.08 M, 3.30 mmol) according to TP1 at 25 °C in 2 h
and addition of CuCN· 2 LiCl (0.90 mL, 30 mol%), the cyclization was carried out according to
TP13 (75 °C, 200 W, 3 h). An allylation reaction was performed according to TP4 using ethyl 2-
(bromomethyl)acrylate (521 mg, 2.70 mmol) at 0 °C within 1 h. Flash column chromatographical
purification on silica gel (pentane/diethyl ether = 8:1) afforded 12r (685 mg, 68%) as a yellow oil. 1H-NMR (CDCl3, 600 MHz): δ = 7.83-7.80 (m, 1H), 7.76-7.73 (m, 1H), 7.38-7.34 (m, 1H),
7.31-7.27 (m, 1H), 6.36 (d, J = 1.10 Hz, 1H), 5.54 (d, J = 1.10 Hz, 1H), 4.25 (q, J = 7.15 Hz, 2H),
4.02 (s, 2H), 1.30 (q, J = 7.15 Hz, 3H), 0.44 (s, 9H). 13C-NMR (CDCl3, 150 MHz): δ = 166.4, 150.7, 143.7, 141.7, 139.9, 133.0, 132.4, 130.4, 126.9,
124.5, 123.9, 123.4, 120.7, 61.0, 33.9, 14.2, 0.0.
IR (Diamond ATR, neat): ν~ = 2957 (w), 2954 (w), 2897 (vw), 1713 (s), 1633 (w), 1475 (w),
1466 (w), 1442 (m), 1403 (w), 1367 (w), 1328 (m), 1312 (w), 1301 (w), 1274 (m), 1248 (s), 1208
(m), 1172 (w), 1140 (m), 1121 (m), 1096 (w), 1068 (w), 1020 (m), 989 (w), 946 (m), 905 (vw), 874
(w), 835 (vs), 748 (s), 724 (m), 709 (w), 695 (w).
MS (EI, 70 eV): m/z = 374 (48) [M+], 345 (60), 331 (12), 228 (40), 73 (100), 59 (21), 45 (12).
HR-MS: (C19H22O2S2Si) calculated: 374.0830 found: 374.0828.
(2-Iodobenzo[b]thieno[2,3-d]thiophen-3-yl)trimethylsilane (12s):
The title compound was prepared from the alkynyl(aryl)thioether 9f (394 mg, 1.50 mmol). After
metalation with TMPMgCl· LiCl (1.53 mL, 1.08 M, 1.65 mmol) according to TP1 at 25 °C in 2 h
and addition of CuCN· 2 LiCl (0.45 mL, 30 mol%), the cyclization was carried out according to
TP13 (75 °C, 200 W, 3 h). An iodination reaction was performed using elemental iodine (343 mg,
1.35 mmol) at 25 °C within 1 h. Flash column chromatographical purification on silica gel
(pentane) afforded 12s (323 mg, 55%) as a yellow oil. 1H-NMR (CDCl3, 400 MHz): δ = 7.82-7.79 (m, 1H), 7.76-7.73 (m, 1H), 7.40-7.30 (m, 2H), 0.55
(s, 9H).
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
124
13C-NMR (CDCl3, 100 MHz): δ = 143.0, 141.7, 139.6, 138.1, 131.3, 124.7, 124.5, 123.5, 121.1,
82.8, 0.1.
IR (Diamond ATR, neat): ν~ = 3047 (w), 2949 (w), 2892 (w), 1593 (w), 1470 (w), 1449 (m),
1420 (m), 1374 (w), 1313 (m), 1293 (m), 1273 (w), 1263 (m), 1246 (s), 1157 (w), 1133 (w), 1069
(m), 1018 (w), 998 (m), 981 (w), 872 (m), 862 (m), 831 (vs), 759 (s), 744 (vs), 722 (s), 709 (m), 695
(m), 662 (w).
MS (EI, 70 eV): m/z = 388 (86) [M+], 373 (37), 246 (31), 171 (15), 71 (40), 57 (52), 43 (100).
HR-MS: (C13H13IS2Si) calculated: 387.9273 found: 387.9274.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
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Transformation of the Silyl Protection Group
(5-Chlorobenzo[b]thiophen-2-yl)(thiophen-2-yl)methanone (13a):
S
OCl
S
The title compound was prepared according to TP14 from 12h (351 g, 1.00 mmol) and TBAF
trihydrate (473 mg, 1.50 mmol) in 1 h. Flash column chromatographical purification on silica gel
(pentane/dichloromethane = 1:1) afforded 13a (239 mg, 85%) as a yellow powder.
Mp. : 168.0-169.7 °C. 1H-NMR (CDCl3, 300 MHz): δ = 8.05 (s, 1H), 7.95 (dd, J = 3.66 Hz, J = 1.10 Hz, 1H), 7.88 (d,
J = 2.02 Hz, 1H), 7.81 (d, J = 8.61 Hz, 1H), 7.75 (dd, J = 5.04 Hz, J = 1.10 Hz, 1H), 7.43 (dd, J =
8.61 Hz, J = 2.02 Hz, 1H), 7.22 (dd, J = 5.04 Hz, J = 3.66 Hz, 1H). 13C-NMR (CDCl3, 75 MHz): δ = 179.7, 144.3, 142.3, 140.2, 140.0, 134.2, 133.7, 131.3, 129.0,
128.2, 127.8, 125.1, 123.9.
IR (Diamond ATR, neat): ν~ = 3103 (vw), 3088 (vw), 1599 (s), 1548 (w), 1516 (w), 1506 (m),
1410 (s), 1355 (m), 1316 (w), 1299 (m), 1290 (m), 1244 (w), 1230 (m), 1179 (m), 1163 (m), 1123
(w), 1096 (m), 1078 (m), 1073 (m), 1065 (m), 1058 (m), 1040 (s), 946 (w), 925 (w), 904 (m), 883
(s), 868 (m), 862 (m), 807 (s), 779 (s), 754 (w), 748 (m), 735 (vs), 728 (s), 713 (vs), 672 (m).
MS (EI, 70 eV): m/z = 278 (70) [M+], 250 (14), 195 (27), 123 (11), 111 (100), 84 (14), 61 (10), 43
(53).
HR-MS: (C13H7OClS2) calculated: 277.9627 found: 277.9636.
(6-Methoxybenzo[b]thiophen-2-yl)(thiophen-2-yl)methanone (13b):
The title compound was prepared according to TP14 from 12a (430 g, 1.25 mmol) and TBAF
trihydrate (595 mg, 1.90 mmol) in 1 h. Flash column chromatographical purification on silica gel
(pentane/dichloromethane = 1:1) afforded 13b (278 mg, 81%) as a yellow powder.
Mp. : 117.3-118.1 °C. 1H-NMR (CDCl3, 300 MHz): δ = 8.04 (s, 1H), 7.93 (dd, J = 3.46 Hz, J = 0.97 Hz, 1H), 7.76 (d,
J = 8.85 Hz, 1H), 7.69 (dd, J = 4.98 Hz, J = 0.97 Hz, 1H), 7.30 (d, J = 2.21 Hz, 1H), 7.18 (dd, J =
4.98 Hz, J = 3.46 Hz, 1H), 7.02 (dd, J = 8.85 Hz, J = 2.21 Hz, 1H), 3.89 (s, 3H).
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
126
13C-NMR (CDCl3, 75 MHz): δ = 179.7, 159.8, 144.5, 142.6, 140.2, 133.3, 133.0, 133.0, 130.4,
127.9, 126.8, 116.1, 104.2, 55.6.
IR (Diamond ATR, neat): ν~ = 2930 (w), 2835 (w), 1598 (m), 1579 (s), 1559 (m), 1521 (m),
1504 (s), 1475 (m), 1451 (m), 1431 (m), 1411 (s), 1350 (m), 1343 (m), 1302 (m), 1295 (m), 1263
(s), 1231 (s), 1224 (s), 1186 (m), 1177 (s), 1153 (m), 1123 (m), 1084 (m), 1058 (m), 1043 (s), 1018
(s), 867 (m), 856 (s), 834 (s), 825 (s), 796 (s), 765 (s), 739 (s), 710 (vs), 687 (m), 665 (m).
MS (EI, 70 eV): m/z = 274 (100) [M+], 259 (10), 191 (27), 111 (40).
HR-MS: (C14H10O2S2) calculated: 274.0122 found: 274.0116.
(5-Chlorobenzo[b]thiophen-2-yl)(furan-2-yl)methanone (13c):
The title compound was prepared according to TP14 from 12e (502 g, 1.50 mmol) and TBAF
trihydrate (710 mg, 2.25 mmol) in 1 h. Flash column chromatographical purification on silica gel
(pentane/dichloromethane = 1:1) afforded 13c (353 mg, 90%) as a white powder.
Mp. : 144.8-146.5 °C. 1H-NMR (CDCl3, 300 MHz): δ = 8.34 (s, 1H), 7.88 (d, J = 2.09 Hz, 1H), 7.79 (d, J = 8.47 Hz,
1H), 7.72 (dd, J = 1.65 Hz, J = 0.77 Hz, 1H), 7.45 (dd, J = 3.63 Hz, J = 0.77 Hz, 1H), 7.41 (dd, J
= 8.47 Hz, J = 2.09 Hz, 1H), 6.64 (dd, J = 3.63 Hz, J = 1.65 Hz, 1H). 13C-NMR (CDCl3, 75 MHz): δ = 174.2, 152.3, 146.8, 143.7, 140.3, 140.3, 131.2, 129.9, 127.8,
125.3, 123.8, 119.5, 112.7.
IR (Diamond ATR, neat): ν~ = 1623 (s), 1566 (m), 1507 (m), 1456 (s), 1415 (w), 1383 (w),
1305 (m), 1279 (w), 1222 (w), 1189 (m), 1156 (m), 1129 (m), 1079 (m), 1064 (w), 1054 (w), 1012
(m), 907 (w), 884 (m), 875 (s), 804 (vs), 757 (vs), 742 (m), 737 (s), 710 (m).
MS (EI, 70 eV): m/z = 262 (100) [M+], 195 (93), 171 (29), 167 (37), 123 (40), 44 (37).
HR-MS: (C13H7O2ClS) calculated: 261.9855 found: 261.9850.
2-Pivaloylbenzo[b]thiophene-5-carbonitrile (13d):
The title compound was prepared according to TP14 from 12l (200 g, 0.64 mmol) and TBAF
trihydrate (316 mg, 1.90 mmol) in 1 h. Flash column chromatographical purification on silica gel
(pentane/diethyl ether = 5:1) afforded 13d (132 mg, 85%) as a yellow powder.
Mp. : 157.6-159.4 °C.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
127
1H-NMR (CDCl3, 300 MHz): δ = 8.19 (s, 1H), 7.94 (d, J = 1.38 Hz, 1H), 7.62 (d, J = 8.57 Hz,
1H), 7.93 (dd, J = 8.57 Hz, J = 1.38 Hz, 1H), 1.45 (s, 9H). 13C-NMR (CDCl3, 75 MHz): δ = 199.8, 145.1, 144.8, 139.0, 130.3, 128.4, 127.6, 123.6, 118.8,
108.7, 44.3, 28.0.
IR (Diamond ATR, neat): ν~ = 3101 (w), 2995 (w), 2969 (m), 2961 (m), 2870 (w), 2224 (w),
1650 (vs), 1599 (m), 1515 (m), 1481 (s), 1459 (m), 1453 (m), 1421 (w), 1395 (w), 1365 (s), 1276
(m), 1262 (w), 1244 (m), 1151 (vs), 1139 (s), 1091 (w), 1075 (m), 1067 (m), 1051 (s), 1021 (m),
942 (w), 937 (w), 904 (s), 888 (s), 871 (m), 822 (s), 798 (m), 753 (w), 720 (m).
MS (EI, 70 eV): m/z = 243 (12600) [M+], 186 (82), 159 (26), 114 (25), 57 (100), 41 (28),
HR-MS: (C14H13ONS) calculated: 243.0718 found: 243.0721.
(4-Chlorophenyl)(6-methoxybenzo[b]thiophen-2-yl)methanone (13e):
The title compound was prepared according to TP14 from 12b (375 g, 1.00 mmol) and TBAF
trihydrate (473 mg, 1.50 mmol) in 1 h. Flash column chromatographical purification on silica gel
(pentane/diethyl ether = 4:1) afforded 13e (288 mg, 95%) as a yellow powder.
Mp. : 138.1-139.9 °C. 1H-NMR (CDCl3, 300 MHz): δ = 7.83 (d, J = 8.75 Hz, 2H), 7.73 (s, 1H), 7.73 (d, J = 8.92 Hz,
1H), 7.49 (d, J = 8.75 Hz, 2H), 7.31 (d, J = 2.31 Hz, 1H), 7.03 (dd, J = 8.92 Hz, J = 2.31 Hz, 1H),
3.90 (s, 3H). 13C-NMR (CDCl3, 75 MHz): δ = 188.0, 160.1, 145.1, 140.4, 138.6, 136.3, 133.0, 132.3, 130.5,
128.8, 127.0, 116.3, 104.3, 55.6.
IR (Diamond ATR, neat): ν~ = 2927 (w), 2360 (w), 1741 (w), 1648 (m), 1595 (m), 1583 (s),
1560 (m), 1554 (m), 1470 (s), 1457 (s), 1449 (s), 1437 (m), 1430 (m), 1395 (m), 1298 (m), 1256 (s),
1238 (s), 1224 (vs), 1185 (m), 1178 (m), 1098 (m), 1085 (s), 1056 (m), 1029 (m), 1012 (m), 949 (s),
895 (m), 855 (m), 843 (m), 839 (m), 831 (m), 825 (s), 807 (s), 760 (m), 743 (s).
MS (EI, 70 eV): m/z = 302 (28) [M+], 191 (17), 84 (49), 74 (76), 59 (100), 45 (54).
HR-MS: (C16H11O2ClS) calculated: 302.0168 found: 302.0170.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
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(4-Chlorophenyl)(6-hydroxybenzo[b]thiophen-2-yl)methanone (13f):
The title compound was prepared according to TP14 from 12c (540 mg, 1.05 mmol) and TBAF
trihydrate (828 mg, 2.63 mmol) in 1 h. Flash column chromatographical purification on silica gel
(dichloromethane to ethyl acetate) afforded 13f (243 mg, 80%) as a dark solid.
Mp. : 168.7-170.2 °C. 1H-NMR (CDCl3, 400 MHz): δ = 10.26 (s, 1H), 7.96 (s, 1H), 7.87 (d, J = 8.75 Hz, 2H), 7.85 (d,
J = 8.77 Hz, 1H), 7.63 (d, J = 8.75 Hz, 2H), 7.34 (d, J = 2.14 Hz, 1H), 6.97 (dd, J = 8.77 Hz, J =
2.14 Hz, 1H). 13C-NMR (CDCl3, 100 MHz): δ = 187.3, 158.4, 144.4, 138.4, 137.2, 136.2, 134.0, 132.0, 130.7,
128.8, 128.0, 116.2, 107.1.
IR (Diamond ATR, neat): ν~ = 2362 (w), 1736 (w), 1627 (m), 1616 (m), 1593 (vs), 1586 (vs),
1563 (s), 1560 (s), 1510 (s), 1507 (s), 1499 (s), 1496 (s), 1483 (s), 1471 (s), 1456 (m), 1436 (s), 1430
(s), 1397 (m), 1369 (m), 1365 (m), 1300 (s), 1279 (s), 1227 (vs), 1217 (vs), 1182 (s), 1168 (s), 1164
(s), 1124 (m), 1105 (vs), 1091 (vs), 1053 (m), 1049 (m), 1010 (s), 857 (s), 839 (s), 834 (vs), 808 (m),
803 (m), 748 (s), 737 (m), 734 (m), 683 (m).
MS (EI, 70 eV): m/z = 288 (100) [M+], 177 (85), 140 (10), 139 (19), 111 (15).
HR-MS: (C15H9O2ClS) calculated: 288.0012 found: 288.0008.
tert-Butyl 2-pivaloylbenzo[b]thiophene-5-carboxylate (13g):
The title compound was prepared according to TP14 from 12m (345 mg, 0.90 mmol) and TBAF
trihydrate (427 mg, 1.35 mmol) in 1 h. Flash column chromatographical purification on silica gel
(pentane/diethyl ether = 6:1) afforded 13g (269 mg, 91%) as a yellow oil.
Mp. : 115.2-117.0 °C. 1H-NMR (CDCl3, 300 MHz): δ = 8.51 (d, J = 1.38 Hz, 1H), 8.05 (s, 1H), 8.03 (dd, J = 8.57 Hz,
J = 1.38 Hz, 1H), 7.85 (d, J = 8.57 Hz, 1H), 1.62 (s, 9H), 1.45 (s, 9H). 13C-NMR (CDCl3, 75 MHz): δ = 200.1, 165.4, 145.1, 143.3, 139.0, 129.0, 129.0, 127.5, 127.3,
122.2, 81.3, 44.2, 28.2, 28.1.
IR (Diamond ATR, neat): ν~ = 2978 (w), 2974 (w), 2930 (w), 1705 (s), 1647 (s), 1598 (w), 1552
(w), 1516 (w), 1477 (w), 1471 (w), 1463 (w), 1456 (w), 1365 (m), 1316 (s), 1276 (w), 1262 (m),
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
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1251 (s), 1162 (m), 1137 (vs), 1096 (s), 1069 (m), 1026 (m), 917 (m), 890 (s), 853 (m), 849 (m),
840 (m), 831 (m), 813 (w), 804 (w), 801 (w), 792 (m), 760 (s), 737 (w), 734 (w), 729 (w).
MS (EI, 70 eV): m/z = 318 (31) [M+], 261 (100), 245 (29), 205 (96), 160 (24), 57 (44).
HR-MS: (C18H22O3S) calculated: 318.1290 found: 318.1275.
(5-Chloro-3-iodobenzo[b]thiophen-2-yl)(thiophen-2-yl)methanone (14a):
The title compound was prepared according to TP15 from 12h (420 mg, 1.20 mmol) and iodine
monochloride (227 mg, 1.40 mmol). Flash column chromatographical purification on silica gel
(pentane/dichloromethane = 2:1) afforded 14a (418 mg, 86%) as a yellow solid.
Mp. : 169.9-171.7 °C. 1H-NMR (CDCl3, 300 MHz): δ = 7.94 (dd, J = 1.98 Hz, J = 0.37 Hz, 1H), 7.83 (dd, J = 3.81
Hz, J = 1.17 Hz, 1H), 7.80 (dd, J = 4.98 Hz, J = 1.17 Hz, 1H), 7.77 (dd, J = 8.65 Hz, J = 0.37 Hz,
1H), 7.46 (dd, J = 8.65 Hz, J = 1.98 Hz, 1H), 7.17 (dd, J = 4.98 Hz, J = 3.81 Hz, 1H). 13C-NMR (CDCl3, 75 MHz): δ = 180.6, 143.2, 142.5, 138.4, 137.3, 136.1, 136.0, 132.8, 128.3,
128.2, 127.1, 123.6, 83.0.
IR (Diamond ATR, neat): ν~ = 3087 (w), 3075 (w), 2920 (w), 1717 (w), 1706 (w), 1700 (w),
1624 (s), 1584 (w), 1580 (w), 1541 (w), 1511 (m), 1504 (m), 1499 (m), 1487 (m), 1427 (w), 1404
(s), 1365 (w), 1352 (s), 1311 (w), 1289 (w), 1266 (m), 1257 (m), 1239 (s), 1192 (m), 1149 (w), 1136
(w), 1096 (m), 1076 (m), 1058 (m), 1038 (m), 951 (m), 944 (m), 883 (w), 875 (w), 864 (m), 857 (s),
847 (m), 818 (w), 793 (m), 781 (m), 773 (m), 751 (w), 731 (vs), 704 (s), 697 (m), 676 (w), 661 (w).
MS (EI, 70 eV): m/z = 404 (96) [M+], 321 (17), 277 (64), 166 (19), 111 (100).
HR-MS: (C13H6OClIS2) calculated: 403.8593 found: 403.8588.
(4-Chlorophenyl)(3-iodo-6-methoxybenzo[b]thiophen-2-yl)methanone (14b):
S
I
MeO
O
Cl
The title compound was prepared according to TP15 from 12b (375 mg, 1.00 mmol) and iodine
monochloride (171 mg, 1.05 mmol). Flash column chromatographical purification on silica gel
(pentane/diethyl ether = 4:1) afforded 14b (332 mg, 77%) as a yellow solid.
Mp. : 183.6-185.6 °C.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
130
1H-NMR (CDCl3, 600 MHz): δ = 7.82 (d, J = 8.80 Hz, 2H), 7.81 (d, J = 8.99 Hz, 1H), 7.46 (d, J
= 8.80 Hz, 2H), 7.24 (d, J = 2.20 Hz, 1H), 7.11 (dd, J = 8.99 Hz, J 2.20 Hz, 1H), 3.91 (s, 3H). 13C-NMR (CDCl3, 150 MHz): δ = 188.6, 160.2, 141.5, 139.6, 136.1, 135.7, 135.0, 131.4, 128.8,
128.7, 117.0, 103.8, 85.9, 55.8.
IR (Diamond ATR, neat): ν~ = 3016 (w), 2930 (w), 2363 (w), 1917 (vw), 1717 (w), 1629 (s),
1604 (s), 1596 (s), 1589 (s), 1563 (m), 1558 (m), 1498 (s), 1477 (s), 1455 (m), 1436 (m), 1428 (m),
1396 (m), 1345 (m), 1301 (m), 1293 (m), 1267 (s), 1225 (s), 1187 (m), 1168 (s), 1133 (m), 1111 (s),
1090 (s), 1054 (s), 1019 (s), 1011 (s), 969 (m), 905 (m), 866 (m), 858 (s), 842 (s), 833 (vs), 823 (s),
815 (s), 806 (s), 748 (s), 734 (m), 690 (m), 683 (m).
MS (EI, 70 eV): m/z = 428 (100) [M+], 317 (40), 302 (24), 139 (28), 74 (52), 59 (67), 45 (40).
HR-MS: (C16H10O2ClIS) calculated: 427.9135 found: 427.9122.
Furan-2-yl(3-iodo-6-((triisopropylsilyl)oxy)benzo[b]thiophen-2-yl)methanone (14c):
The title compound was prepared according to TP15 from 12d (380 mg, 0.80 mmol) and iodine
monochloride (162 mg, 1.00 mmol). Flash column chromatographical purification on silica gel
(pentane/diethyl ether = 5:1) afforded 14c (320 mg, 76%) as an orange solid.
Mp. : 60.0-63.6 °C. 1H-NMR (CDCl3, 300 MHz): δ = 7.84 (d, J = 8.85 Hz, 1H), 7.71 (dd, J = 1.66 Hz, J = 0.55 Hz,
1H), 7.42 (dd, J = 3.59 Hz, J = 0.55 Hz, 1H), 7.28 (d, J = 2.21 Hz, 1H), 7.07 (dd, J = 8.85 Hz, J =
2.12 Hz, 1H), 6.61 (dd, J = 3.59 Hz, J = 1.66 Hz, 1H), 1.37-1.26 (m, 3H), 1.17-1.08 (m, 18H). 13C-NMR (CDCl3, 75 MHz): δ = 174.7, 156.9, 152.0, 147.2, 141.2, 135.8, 132.4, 128.8, 120.8,
120.8, 112.6, 111.4, 86.3, 17.9, 12.7.
IR (Diamond ATR, neat): ν~ = 2942 (m), 2888 (w), 2864 (m), 1708 (w), 1640 (m), 1592 (s),
1563 (m), 1554 (m), 1543 (m), 1458 (vs), 1389 (m), 1384 (m), 1294 (m), 1265 (vs), 1232 (m), 1214
(m), 1169 (m), 1155 (m), 1128 (m), 1101 (m), 1083 (m), 1071 (m), 1027 (m), 1014 (m), 997 (m),
965 (m), 939 (s), 919 (m), 904 (s), 882 (vs), 866 (m), 851 (s), 817 (m), 765 (s), 751 (vs), 729 (m),
686 (m), 663 (s).
MS (EI, 70 eV): m/z = 526 (100) [M+], 483 (94), 427 (63), 413 (30), 357 (19), 286 (26), 214 (24).
HR-MS: (C22H27O3ISSi) calculated: 526.0495 found: 526.0482.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
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Ethyl 2-((5-chloro-3-iodobenzo[b]thiophen-2-yl)methyl)acrylate (14d):
The title compound was prepared according to TP15 from 12g (353 mg, 1.00 mmol) and iodine
monochloride (179 mg, 1.10 mmol). Flash column chromatographical purification on silica gel
(pentane/diethyl ether = 6:1) afforded 14d (376 mg, 93%) as a yellow solid.
Mp. : 82.7-84.5 °C. 1H-NMR (CDCl3, 400 MHz): δ = 7.70 (d, J = 2.05 Hz, 1H), 7.62 (d, J = 8.58 Hz, 1H), 7.29 (dd,
J = 8.58 Hz, J = 2.05 Hz, 1H), 6.33 (d, J = 1.00 Hz, 1H), 5.62 (d, J = 1.00 Hz, 1H), 4.23 (q, J =
7.21 Hz, 2H), 3.95 (s, 2H), 1.30 (q, J = 7.21 Hz, 3H). 13C-NMR (CDCl3, 100 MHz): δ = 166.1, 142.8, 142.5, 137.0, 136.7, 131.6, 127.5, 125.6, 125.0,
123.3, 80.9, 61.2, 35.2, 14.2.
IR (Diamond ATR, neat): ν~ = 2999 (w), 2976 (w), 2933 (w), 1697 (vs), 1663 (w), 1652 (w),
1631 (m), 1585 (w), 1462 (w), 1445 (w), 1430 (m), 1422 (m), 1406 (w), 1392 (m), 1369 (m), 1335
(s), 1296 (w), 1288 (m), 1251 (m), 1244 (w), 1204 (vs), 1169 (m), 1147 (s), 1091 (m), 1075 (m),
1066 (m), 1020 (m), 975 (m), 958 (m), 939 (m), 927 (m), 878 (w), 851 (m), 821 (m), 798 (s), 788
(s), 781 (m), 732 (w), 714 (m), 654 (w).
MS (EI, 70 eV): m/z = 406 (15) [M+], 279 (100), 251 (27), 171 (43), 57 (15), 43 (16).
HR-MS: (C14H12O2ClIS) calculated: 405.9291 found: 405.9280.
tert-Butyl 2-(furan-2-carbonyl)-3-iodobenzo[b]thiophene-5-carboxylate (14e):
The title compound was prepared according to TP15 from 12n (672 mg, 1.68 mmol) and iodine
monochloride (327 mg, 2.00 mmol). Flash column chromatographical purification on silica gel
(pentane/diethyl ether = 2:1) afforded 14e (557 mg, 73%) as a yellow solid.
Mp. : 100.9-102.8 °C. 1H-NMR (CDCl3, 300 MHz): δ = 8.61 (d, J = 1.52 Hz, 1H), 8.09 (dd, J = 8.57 Hz, J = 1.52 Hz,
1H), 7.86 (d, J = 8.57 Hz, 1H), 7.73 (dd, J = 1.66 Hz, J = 0.83 Hz, 1H), 7.41 (dd, J = 3.59 Hz, J =
0.83 Hz, 1H), 6.63 (dd, J = 3.59 Hz, J = 1.66 Hz, 1H), 1.65 (s, 9H). 13C-NMR (CDCl3, 75 MHz): δ = 174.9, 165.1, 151.6, 147.8, 143.3, 141.1, 136.2, 130.3, 129.5,
128.0, 122.3, 121.6, 112.8, 86.4, 81.7, 28.2.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
132
IR (Diamond ATR, neat): ν~ = 3115 (vw), 2979 (w), 2929 (w), 1711 (s), 1684 (w), 1640 (m),
1633 (m), 1600 (w), 1560 (m), 1495 (w), 1471 (m), 1457 (s), 1436 (w), 1415 (m), 1387 (m), 1373
(m), 1368 (m), 1363 (m), 1337 (w), 1315 (s), 1293 (s), 1275 (m), 1262 (w), 1242 (s), 1236 (s), 1229
(s), 1151 (s), 1119 (m), 1096 (vs), 1077 (m), 1065 (m), 1032 (m), 1020 (m), 1012 (s), 983 (m), 978
(m), 938 (m), 905 (w), 884 (m), 878 (m), 871 (m), 858 (m), 847 (m), 828 (m), 811 (w), 807 (w), 793
(m), 786 (m), 775 (m), 761 (s), 751 (vs), 740 (s), 727 (m), 714 (m), 707 (m).
MS (EI, 70 eV): m/z = 454 (58) [M+], 398 (100), 272 (23), 128 (45), 95 (29), 56 (17), 41 (28).
HR-MS: (C18H15O4IS) calculated: 453.9736 found: 453.9728.
3-Iodobenzo[b]thieno[2,3-d]thiophene (14f):
The title compound was prepared according to TP15 from 12p (300 mg, 1.14 mmol) and iodine
monochloride (223 mg, 1.37 mmol). Flash column chromatographical purification on silica gel
(pentane) afforded 14f (280 mg, 77%) as a pale yellow solid.
Mp. : 88.8-90.7 °C. 1H-NMR (CDCl3, 300 MHz): δ = 7.89-7.77 (m, 2H), 7.52 (s, 1H), 7.46-7.34 (m, 2H). 13C-NMR (CDCl3, 75 MHz): δ = 144.1, 142.2, 134.1, 133.3, 130.1, 124.9, 124.9, 124.1, 121.4,
85.9.
IR (Diamond ATR, neat): ν~ = 3093 (w), 2951 (w), 1455 (m), 1431 (m), 1404 (w), 1338 (m),
1320 (w), 1295 (w), 1250 (m), 1127 (w), 1068 (w), 1064 (w), 1019 (w), 1006 (w), 995 (w), 967 (w),
917 (m), 839 (s), 825 (m), 750 (vs), 718 (s), 701 (m).
MS (EI, 70 eV): m/z = 316 (100) [M+], 189 (42), 128 (10), 44 (31).
HR-MS: (C10H5IS2) calculated: 315.8877 found: 315.8869.
tert-Butyl 2-(2-(ethoxycarbonyl)allyl)-3-iodobenzo[b]thiophene-5-carboxylate (14g):
The title compound was prepared according to TP15 from 12o (558 mg, 1.33 mmol) and iodine
monochloride (260 mg, 1.60 mmol). Flash column chromatographical purification on silica gel
(pentane/diethyl ether = 4:1) afforded 14g (476 mg, 76%) as a yellow oil. 1H-NMR (CDCl3, 300 MHz): δ = 8.34 (d, J = 1.38 Hz, 1H), 7.93 (dd, J = 8.43 Hz, J = 1.38 Hz,
1H), 7.73 (d, J = 8.43 Hz, 1H), 6.33 (d, J = 1.11 Hz, 1H), 5.62 (d, J = 1.11 Hz, 1H), 4.23 (q, J =
7.19 Hz, 2H), 3.97 (s, 2H), 1.64 (s, 9H), 1.29 (q, J = 7.19 Hz, 3H).
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
133
13C-NMR (CDCl3, 75 MHz): δ = 166.1, 165.6, 142.6, 141.8, 141.0, 137.1, 129.3, 127.4, 126.9,
125.6, 122.0, 82.6, 81.3, 61.1, 35.2, 28.2, 14.2.
IR (Diamond ATR, neat): ν~ = 2975 (w), 2930 (w), 1707 (vs), 1652 (vw), 1631 (w), 1616 (vw),
1598 (w), 1476 (w), 1456 (w), 1442 (w), 1422 (m), 1405 (w), 1391 (w), 1366 (m), 1313 (s), 1294 (s),
1242 (s), 1211 (m), 1159 (vs), 1096 (vs), 1064 (w), 1024 (m), 973 (m), 949 (m), 933 (w), 906 (w),
846 (m), 829 (w), 816 (w), 790 (vw), 757 (s), 731 (m), 726 (m), 720 (m).
MS (EI, 70 eV): m/z = 472 (30) [M+], 399 (44), 345 (100), 289 (85), 261 (55), 215 (32), 171 (56),
57 (39).
HR-MS: (C19H21O4IS) calculated: 472.0205 found: 472.0207.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
134
Further Functionalization of the Benzo[b]thiophene Scaffold
Ethyl 2-((6-methoxy-2-(thiophene-2-carbonyl)benzo[b]thiophen-3-yl)methyl)acrylate
(15a):
The title compound was prepared according to TP1 from 13b (138 mg, 0.50 mmol) and
TMPMgCl· LiCl (0.51 mL, 1.08 M, 0.55 mmol) at -30 °C in 3 h. An allylation reaction was
performed according to TP4 using ethyl 2-(bromomethyl)acrylate (97 mg, 0.55 mmol) at -30 °C
in 1 h. Flash column chromatographical purification on silica gel (pentane/dichloromethane =
2:1) afforded 15a (155 mg, 80%) as a red solid.
Mp. : 106.8-108.6 °C. 1H-NMR (CDCl3, 300 MHz): δ = 8.00 (s, 1H), 7.78 (d, J = 3.81 Hz, 1H), 7.75 (d, J = 8.80 Hz,
1H), 7.29 (d, J = 2.35 Hz, 1H), 7.02 (dd, J = 8.80 Hz, J = 2.35 Hz, 1H), 6.94 (d, J = 3.81 Hz, 1H),
6.32 (d, J = 0.88 Hz, 1H), 5.69 (d, J = 0.88 Hz, 1H), 4.22 (q, J = 7.19 Hz, 2H), 3.88 (s, 3H), 3.87
(s, 2H), 1.29 (t, J = 7.19 Hz, 3H). 13C-NMR (CDCl3, 75 MHz): δ = 179.3, 166.1, 159.7, 151.0, 144.4, 141.1, 140.1, 138.6, 133.5,
133.0, 130.0, 127.0, 126.9, 126.7, 116.0, 104.2, 61.1, 55.6, 32.9, 14.1.
IR (Diamond ATR, neat): ν~ = 2961 (w), 2837 (w), 1711 (vs), 1628 (w), 1599 (s), 1576 (m),
1559 (w), 1532 (w), 1506 (s), 1476 (m), 1464 (w), 1445 (s), 1404 (m), 1366 (w), 1342 (w), 1308 (w),
1295 (s), 1262 (vs), 1225 (vs), 1202 (s), 1179 (s), 1172 (s), 1140 (s), 1118 (s), 1083 (m), 1061 (m),
1058 (m), 1026 (vs), 1021 (vs), 953 (m), 926 (w), 850 (m), 806 (s), 798 (vs), 776 (m), 764 (m), 745
(m), 737 (s), 714 (m), 675 (w).
MS (EI, 70 eV): m/z = 386 (100) [M+], 341 (5), 312 (10), 191 (45), 149 (7).
HR-MS: (C20H18O4S2) calculated: 386.0647 found: 386.0641.
Ethyl 2-(4-chlorobenzoyl)-6-methoxybenzo[b]thiophene-3-carboxylate (15b):
SMeO
O
Cl
CO2Et
The title compound was prepared according to TP1 from 13e (300 mg, 1.00 mmol) and
TMPMgCl· LiCl (1.10 mL, 1.08 M, 1.20 mmol) at -40 °C in 5 h, when ethyl cyanoformate (129
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
135
mg, 1.30 mmol) was added and the mixture stirred for 1 h while warming to 25 °C. Flash column
chromatographical purification on silica gel (pentane/diethyl ether = 4:1) afforded 15b (292 mg,
78%) as a yellow solid.
Mp. : 130.6-132.1 °C. 1H-NMR (CDCl3, 600 MHz): δ = 8.31 (d, J = 8.99 Hz, 1H), 7.80 (d, J = 8.80 Hz, 2H), 7.43 (d, J
= 8.80 Hz, 2H), 7.30 (d, J = 2.20 Hz, 1H), 7.11 (dd, J = 8.99 Hz, J 2.20 Hz, 1H), 3.99 (q, J = 7.15
Hz, 2H), 3.90 (s, 3H), 0.99 (q, J = 7.15 Hz, 3H). 13C-NMR (CDCl3, 150 MHz): δ = 189.0, 162.4, 159.0, 143.4, 141.2, 139.9, 136.0, 130.8, 130.6,
128.9, 127.6, 126.2, 116.6, 104.0, 61.3, 55.6, 13.5.
IR (Diamond ATR, neat): ν~ = 3071 (vw), 2970 (w), 2935 (w), 1740 (w), 1734 (w), 1713 (s),
1647 (m), 1600 (m), 1583 (m), 1568 (m), 1505 (m), 1485 (m), 1475 (m), 1462 (m), 1453 (m), 1435
(w), 1412 (w), 1398 (w), 1383 (w), 1368 (w), 1333 (w), 1285 (w), 1265 (s), 1228 (vs), 1201 (s), 1174
(m), 1129 (m), 1106 (s), 1091 (s), 1079 (m), 1053 (s), 1038 (m), 1023 (s), 1011 (s), 984 (w), 968
(w), 910 (m), 883 (m), 861 (m), 853 (s), 840 (m), 833 (m), 822 (vs), 777 (w), 731 (s), 716 (w), 680
(m).
MS (EI, 70 eV): m/z = 374 (100) [M+], 329 (21), 235 (33), 191 (14), 139 (25), 111 (19), 59 (11).
HR-MS: (C19H15O4ClS) calculated: 374.0380 found: 374.0376.
4-(5-Chloro-2-(thiophene-2-carbonyl)benzo[b]thiophen-3-yl)butyl acetate (16a):
The title compound was prepared according to TP3 from (4-acetoxybutyl)zinc bromide43b,61
(0.77 mL, 0.78 M, 0.60 mmol), 14a (203 mg, 0.50 mmol), Pd(OAc)2 (3.00 mg, 2 mol%) and S-
Phos (8.00 mg, 4 mol%) at 25 °C in 1 h. Flash column chromatographical purification on silica
gel (pentane/ ethyl acetate = 10:1) afforded 16a (151 mg, 77%) as a yellow oil. 1H-NMR (CDCl3, 300 MHz): δ = 7.91 (dd, J = 1.11 Hz, J = 3.87 Hz, 1H), 7.84 (dd, J = 1.94
Hz, J = 0.55 Hz, 1H), 7.78 (dd, J = 8.57 Hz, J = 0.55 Hz, 1H), 7.74 (dd, J = 4.98 Hz, J = 1.11 Hz,
1H), 7.44 (dd, J = 8.57 Hz, J = 1.94 Hz, 1H), 7.16 (dd, J = 4.98 Hz, J = 3.87 Hz, 1H), 4.14-4.04
(m, 2H), 3.18-3.07 (m, 2H), 2.03 (s, 3H), 1.83-1.71 (m, 4H). 13C-NMR (CDCl3, 75 MHz): δ = 181.3, 171.2, 145.0, 142.7, 140.5, 138.4, 134.8, 134.7, 134.6,
131.3, 128.1, 127.5, 123.8, 123.1, 64.0, 28.5, 27.2, 26.6, 21.0.
IR (Diamond ATR, neat): ν~ = 3089 (vw), 2946 (w), 2865 (w), 1730 (s), 1685 (vw), 1652 (vw),
1618 (m), 1584 (w), 1548 (w), 1514 (m), 1471 (w), 1456 (w), 1436 (w), 1409 (s), 1387 (w), 1362
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
136
(m), 1353 (m), 1265 (s), 1239 (vs), 1150 (w), 1128 (vw), 1100 (w), 1078 (m), 1058 (m), 1046 (m),
1017 (m), 974 (w), 948 (w), 916 (w), 893 (w), 862 (m), 801 (s), 750 (m), 723 (s), 675 (w), 656 (vw).
MS (EI, 70 eV): m/z = 392 (93) [M+], 304 (34), 271 (21), 221 (35), 111 (100), 43 (31).
HR-MS: (C19H17O3ClS2) calculated: 392.0308 found: 392.0299.
Ethyl 4-(5-chloro-2-(thiophene-2-carbonyl)benzo[b]thiophen-3-yl)butanoate (16b):
The title compound was prepared according to TP3 from (4-ethoxy-4-oxobutyl)zinc bromide43,61
(0.60 mL, 0.75 M, 0.45 mmol), 14a (167 mg, 0.41 mmol), Pd(OAc)2 (2.00 mg, 2 mol%) and S-
Phos (7.00 mg, 4 mol%) at 25 °C in 1 h. Flash column chromatographical purification on silica
gel (pentane/diethyl ether = 6:1) afforded 16b (126 mg, 78%) as a yellow oil. 1H-NMR (CDCl3, 300 MHz): δ = 7.94 (d, J = 1.94 Hz, 1H), 7.92 (dd, J = 3.87 Hz, J = 1.11 Hz,
1H), 7.77 (d, J = 8.57 Hz, 1H), 7.73 (dd, J = 4.98 Hz, J = 1.11 Hz, 1H), 7.43 (dd, J = 8.57 Hz,
J = 1.94 Hz, 1H), 7.16 (dd, J = 4.98 Hz, J = 3.87 Hz, 1H), 4.14 (q, J = 7.00 Hz, 2H), 3.19-3.11
(m, 2H), 2.46-2.38 (m, 2H), 2.10-1.97 (m, 2H), 1.25 (t, J = 7.00 Hz, 3H). 13C-NMR (CDCl3, 75 MHz): δ = 181.1, 173.2, 144.9, 142.3, 142.2, 140.5, 138.3, 134.8, 134.7,
131.4, 128.1, 127.5, 123.7, 123.3, 60.4, 33.8, 26.9, 25.2, 14.2.
IR (Diamond ATR, neat): ν~ = 3093 (vw), 2974 (w), 2937 (w), 2933 (w), 2360 (vw), 1725 (vs),
1616 (s), 1584 (w), 1514 (s), 1452 (w), 1443 (w), 1409 (vs), 1373 (m), 1352 (s), 1266 (vs), 1244
(vs), 1192 (s), 1153 (s), 1113 (w), 1094 (w), 1079 (s), 1061 (s), 1045 (s), 1027 (s), 924 (m), 896 (w),
862 (m), 800 (s), 750 (m), 722 (vs), 674 (w).
MS (EI, 70 eV): m/z = 392 (42) [M+], 305 (29), 291 (31), 256 (30), 227 (27), 111 (100).
HR-MS: (C19H17O3ClS2Na) calculated: 415.0206 found: 415.0201.
Furan-2-yl(3-(4-methoxyphenyl)-6-((triisopropylsilyl)oxy)benzo[b]thiophen-2-yl)methan-
one (16c):
The title compound was prepared according to TP3 from (4-methoxyphenyl)zinc bromide54 (0.71
mL, 0.85 M, 0.60 mmol), 14c (264 mg, 0.50 mmol), Pd(OAc)2 (3.00 mg, 2 mol%) and S-Phos
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
137
(8.00 mg, 4 mol%) at 25 °C in 1 h. Flash column chromatographical purification on silica gel
(pentane/diethyl ether = 6:1) afforded 16c (206 mg, 80%) as a yellow oil. 1H-NMR (CDCl3, 300 MHz): δ = 7.60 (d, J = 9.12 Hz, 1H), 7.39-7.34 (m, 2H), 7.33 (d,
J = 8.57 Hz, 2H), 7.01-6.94 (m, 2H) 6.90 (d, J = 8.57 Hz, 2H), 6.34 (dd, J = 3.59 Hz, J = 1.66 Hz,
1H), 3.05 (s, 3H), 1.36-1.25 (m, 3H), 1.20-1.06 (m, 18H). 13C-NMR (CDCl3, 75 MHz): δ = 176.9, 159.3, 155.9, 152.0, 146.5, 142.2, 141.6, 133.8, 133.1,
131.0, 127.4, 125.9, 119.8, 119.6, 113.8, 112.0, 111.8, 55.3, 17.9, 12.7.
IR (Diamond ATR, neat): ν~ = 2942 (m), 2891 (w), 2865 (m), 2360 (vw), 1734 (vw), 1717 (vw),
1627 (m), 1623 (m), 1608 (m), 1593 (s), 1563 (m), 1525 (s), 1490 (m), 1460 (vs), 1415 (w), 1389
(m), 1365 (w), 1346 (m), 1267 (vs), 1246 (vs), 1229 (s), 1189 (m), 1174 (s), 1163 (m), 1127 (w),
1110 (m), 1076 (w), 1052 (w), 1030 (m), 1013 (m), 996 (w), 974 (w), 942 (s), 913 (s), 882 (s), 863
(m), 852 (m), 831 (m), 820 (m), 803 (m), 783 (w), 757 (s), 732 (m), 679 (s).
MS (EI, 70 eV): m/z = 506 (100) [M+], 463 (35), 435 (17), 407 (27), 393 (17), 368 (17), 204 (31),
196 (13), 188 (17).
HR-MS: (C29H34O4SSi) calculated: 506.1947 found: 506.1937.
(4-(Benzo[b]thieno[2,3-d]thiophen-3-yl)phenyl)trimethylsilane (16d):
The title compound was prepared according to TP3 from (4-(trimethylsilyl)phenyl)zinc bromide54
(0.70 mL, 0.60 M, 0.42 mmol), 14f (120 mg, 0.38 mmol), Pd(dba)2 (7.00 mg, 3 mol%) and tfp
(6.00 mg, 6 mol%) at 25 °C in 1 h. Flash column chromatographical purification on silica gel
(pentane) afforded 16d (97 mg, 75%) as a white solid.
Mp. : 86.5-88.6 °C. 1H-NMR (CDCl3, 300 MHz): δ = 7.93-7.86 (m, 2H), 7.82-7.76 (m, 2H), 7.70-7.65 (m, 2H), 7.60
(s, 1H), 7.48-7.34 (m, 2H), 0.35 (s, 9H). 13C-NMR (CDCl3, 75 MHz): δ = 142.1, 140.1, 136.6, 135.4, 135.1, 135.0, 134.0, 132.7, 125.7,
124.7, 124.5, 123.8, 122.9, 120.7, -1.1.
IR (Diamond ATR, neat): ν~ = 2948 (w), 2363 (vw), 1739 (w), 1597 (w), 1441 (w), 1404 (w),
1356 (w), 1247 (m), 1242 (m), 1213 (w), 1116 (w), 1103 (m), 941 (w), 835 (s), 819 (s), 782 (w), 749
(vs), 724 (s), 709 (m), 693 (m), 672 (w).
MS (EI, 70 eV): m/z = 338 (54) [M+], 323 (100), 247 (5), 162 (18), 73 (6), 43 (8).
HR-MS: (C19H18S2Si) calculated: 338.0619 found: 338.0622.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
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Ethyl 2-((5-chloro-3-(furan-2-carbonyl)benzo[b]thiophen-2-yl)methyl)acrylate (15c):
An I/Mg-exchange was performed according to TP6 using 14d (203 mg, 0.50 mmol) and
i-PrMgCl· LiCl (0.41 mL, 1.34 M, 0.55 mmol) at -80 °C within 10 min. An acylation reaction was
performed according to TP4 using furan 2-carbonyl chloride (60 mg, 0.45 mmol) at -30 °C
within 2 h. Flash column chromatographical purification on silica gel (pentane/diethyl ether =
6:1) afforded 15c (129 mg, 77%) as a white solid.
Mp. : 131.8-133.7 °C. 1H-NMR (CDCl3, 300 MHz): δ = 7.71-7.65 (m, 2H), 7.57 (dd, J = 2.00 Hz, J =0.48 Hz, 1H),
7.27 (dd, J = 8.58 Hz, J =2.00 Hz, 1H), 7.17 (dd, J = 3.62 Hz, J =0.76 Hz, 1H), 6.58 (dd,
J = 3.62 Hz, J =1.72 Hz, 1H), 6.28 (d, J = 0.76 Hz, 1H), 5.65 (d, J = 0.76 Hz, 1H), 4.14 (q, J =
7.06 Hz, 2H), 3.95 (s, 2H), 1.21 (q, J = 7.06 Hz, 3H). 13C-NMR (CDCl3, 75 MHz): δ = 179.1, 165.9, 152.9, 148.7, 147.6, 139.5, 137.9, 136.3, 131.6,
131.2, 127.8, 125.1, 122.9, 122.7, 120.8, 112.7, 61.1, 31.9, 14.0.
IR (Diamond ATR, neat): ν~ = 3744 (vw), 2966 (w), 2917 (w), 2360 (s), 2357 (s), 2341 (m),
1726 (vs), 1700 (m), 1683 (w), 1665 (vs), 1652 (m), 1550 (w), 1539 (w), 1456 (m), 1447 (m), 1436
(m), 1419 (s), 1376 (w), 1365 (w), 1327 (m), 1303 (m), 1222 (w), 1206 (vs), 1173 (m), 1159 (s),
1074 (s), 1056 (m), 1035 (s), 1013 (m), 981 (m), 950 (s), 932 (m), 904 (w), 884 (s), 858 (m), 841
(m), 821 (w), 814 (m), 804 (s), 788 (m), 762 (m), 743 (m), 725 (w), 717 (s), 709 (m), 683 (m).
MS (EI, 70 eV): m/z = 374 (57) [M+], 356 (52), 302 (34), 274 (69), 237 (16), 208 (36), 171 (17),
95 (100).
HR-MS: (C19H15O4ClS) calculated: 374.0380 found: 374.0371.
Ethyl benzo[b]thieno[2,3-d]thiophene-3-carboxylate (15d):
An I/Mg-exchange was performed according to TP6 using 14f (120 mg, 0.38 mmol) and
i-PrMgCl· LiCl (0.31 mL, 1.34 M, 0.42 mmol) at -80 °C within 10 min. Ethyl cyanoformate (46
mg, 0.46 mmol) was added at -80 °C and the mixture stirred for 2 h while warming to 25 °C.
Flash column chromatographical purification on silica gel (pentane/diethyl ether = 8:1) afforded
15d (78 mg, 78%) as a pale yellow solid.
Mp. : 96.6-97.7 °C.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
139
1H-NMR (CDCl3, 300 MHz): δ = 8.25 (s, 1H), 8.27-8.23 (m, 2H), 7.92-7.79 (m, 2H), 4.43 (q, J
= 7.19 Hz, 2H), 1.46 (q, J = 7.19 Hz, 3H). 13C-NMR (CDCl3, 75 MHz): δ = 161.8, 143.3, 138.1, 134.4, 134.3, 132.1, 126.9, 124.8, 124.7,
123.9, 120.6, 61.2, 14.3.
IR (Diamond ATR, neat): ν~ = 3114 (w), 2992 (w), 2979 (w), 2931 (w), 1694 (s), 1498 (m),
1442 (m), 1395 (m), 1377 (m), 1256 (m), 1226 (s), 1171 (w), 1089 (w), 1039 (s), 1016 (m), 974 (w),
859 (m), 850 (w), 831 (w), 758 (vs), 746 (m), 722 (m).
MS (EI, 70 eV): m/z = 262 (100) [M+], 234 (54), 217 (35), 189 (30), 145 (30), 73 (16).
HR-MS: (C13H10O2S2) calculated: 262.0122 found: 262.0110.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
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Cyclization of TIPS-protected Alkynyl(aryl)thioethers
Ethyl 6-methoxy-3-(((triisopropylsilyl)oxy)methyl)benzo[b]thiophene-2-carboxylate (46a)
SCO2Et
MeO
OTIPS
The title compound was prepared from the alkynyl(aryl)thioether 43a (1.29 g, 3.00 mmol)
according to TP6 with i-PrMgCl· LiCl (2.79 mL, 1.29 M, 3.6 mmol) at 25 °C. Cyclization time:
20 h. Ethyl cyanoformate (268 mg, 2.70 mmol) was added at 0 °C and the reaction mixture
stirred for 2 h while warming to 25 °C. Flash column chromatographical purification on silica gel
(pentane/diethyl ether = 20:1) afforded 46a (861 mg, 76%) as a white solid.
Mp. : 59.4-60.7 °C. 1H-NMR (CDCl3, 300 MHz): δ =8.21 (d, J = 8.99 Hz, 1H), 7.21 (d, J = 2.20 Hz, 1H), 7.00 (dd,
J = 8.99 Hz, J = 2.20 Hz, 1H), 5.47 (s, 2H), 4.36 (q, , J = 7.03 Hz, 2H), 3.87 (s, 3H), 1.38 (t, , J =
7.03 Hz, 3H), 1.24-1.10 (m, 3H), 1.06 (s, 18H). 13C-NMR (CDCl3, 75 MHz): δ =163.0, 159.4, 143.5, 142.4, 133.9, 127.2, 124.7, 115.0, 103.8,
61.2, 58.7, 55.5, 18.0, 14.3, 12.0.
IR (Diamond ATR, neat): ν~ = 2956 (w), 2938 (m), 2864 (m), 1709 (s), 1603 (m), 1527 (m),
1465 (m), 1460 (m), 1377 (w), 1269 (m), 1256 (s), 1244 (s), 1210 (vs), 1185 (m), 1106 (m), 1079
(m), 1055 (vs), 1047 (s), 1026 (m), 1012 (m), 1001 (m), 880 (m), 837 (m), 827 (s), 800 (m), 760
(m), 752 (w), 683 (m), 674 (m).
MS (EI, 70 eV): m/z = 422 (1) [M+], 379 (100), 351 (23), 221 (12), 103 (16), 75 (16), 43 (15).
HR-MS: (C22H34O4SSi) calculated: 422.1947 found: 422.1935.
(4-Fluorophenyl)(6-methoxy-3-(((triisopropylsilyl)oxy)methyl)benzo[b]-thiophen-2-yl)-
methanone (46b):
The title compound was prepared from the alkynyl(aryl)thioether 43a (1.29 g, 3.00 mmol)
according to TP6 with i-PrMgCl· LiCl (2.79 mL, 1.29 M, 3.6 mmol) at 25 °C. Cyclization time:
20 h. An acylation reaction was performed according to TP4 using 4-fluorobenzoyl chloride
(428 mg, 2.70 mmol) at 0 °C within 1 h. Flash column chromatographical purification on silica
gel (pentane/diethyl ether = 20:1) afforded 46b (945 mg, 74%) as a light yellow oil.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
141
1H-NMR (CDCl3, 300 MHz): δ = 8.20 (d, J = 8.99 Hz, 1H), 7.90 (dd, J = 8.90 Hz, J = 5.41 Hz,
2H), 7.23 (d, J = 2.38 Hz, 1H), 7.14 (t, J = 8.90 Hz, 2H), 7.05 (dd, J = 8.99 Hz, J = 2.38 Hz, 1H),
5.19 (s, 2H), 3.89 (s, 3H), 1.14-1.02 (m, 3H), 0.99 (s, 18H). 13C-NMR (CDCl3, 75 MHz): δ = 189.1, 165.5, 159.4, 142.8, 142.5, 135.8, 133.6, 132.5, 132.1,
127.1, 115.4, 115.3, 103.7, 59.5, 55.6, 17.9, 11.9.
IR (Diamond ATR, neat): ν~ = 2941 (m), 2888 (w), 2863 (m), 1637 (m), 1597 (s), 1502 (s),
1461 (m), 1346 (m), 1265 (s), 1223 (vs), 1154 (s), 1121 (w), 1087 (m), 1069 (m), 1057 (s), 1043 (s),
1013 (m), 993 (m), 926 (w), 881 (s), 845 (m), 827 (m), 795 (m), 762 (m), 734 (m), 682 (m).
MS (EI, 70 eV): m/z = 472 (4) [M+], 429 (100), 299 (26), 131 (15), 123 (19), 103 (15), 75 (20), 59
(17), 43 (32).
HR-MS: (C26H33O3FSSi) calculated: 472.1904 found: 472.1906.
((2-(2-Bromophenyl)-6-methoxybenzo[b]thiophen-3-yl)methoxy)triiso-propylsilane (46c):
The title compound was prepared from the alkynyl(aryl)thioether 43a (1.29 g, 3.00 mmol)
according to TP6 with i-PrMgCl· LiCl 2.79 mL, 1.29 M, 3.6 mmol) at 25 °C. Cyclization time:
20 h. An cross-coupling reaction was performed according to TP3 using Pd(dba)2 (52 mg,
3 mol%), tfp (42 mg, 6 mol%) and 1-bromo-2-iodobenzene (764 mg, 2.70 mmol) at 25 °C within
3 h. Flash column chromatographical purification on silica gel (pentane/diethyl ether = 20:1)
afforded 46c (1.18 g, 87%) as a colorless oil. 1H-NMR (CDCl3, 300 MHz): δ = 7.95 (d, J = 8.80 Hz, 1H), 7.70-7.63 (m, 1H), 7.50-7.43 (m,
1H), 7.39-7.21 (m, 3H), 7.04 (dd, J = 8.80 Hz, J = 2.38 Hz, 1H), 4.76 (s, 2H), 3.88 (s, 3H), 1.13-
0.98 (m, 21H). 13C-NMR (CDCl3, 75 MHz): δ = 157.5, 141.0, 135.6, 134.9, 133.5, 133.0, 132.8, 129.9, 126.9,
125.1, 124.5, 116.7, 114.1, 104.5, 58.9, 55.6, 18.0, 12.0.
IR (Diamond ATR, neat): ν~ = 2939 (m), 2889 (m), 2862 (m), 1603 (m), 1543 (w), 1479 (m),
1461 (s), 1436 (m), 1382 (w), 1284 (w), 1266 (s), 1239 (s), 1212 (s), 1133 (w), 1099 (s), 1052 (vs),
1045 (vs), 1023 (s), 1013 (m), 1001 (s), 935 (w), 882 (s), 847 (w), 827 (s), 801 (m), 778 (m), 748
(vs), 734 (m), 678 (s).
MS (EI, 70 eV): m/z = 504 (5) [M+], 463 (16), 333 (17), 252 (100), 237 (34).
HR-MS: (C25H33O2SSi) calculated: 504.1154 found: 504.1150.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
142
4-Amino-3-(6-methoxy-3-(((triisopropylsilyl)oxy)methyl)benzo[b]thiophen-2-yl)benzo-
nitrile (46d):
The title compound was prepared from the alkynyl(aryl)thioether 43a (1.29 g, 3.00 mmol)
according to TP6 with i-PrMgCl· LiCl (2.79 mL, 1.29 M, 3.6 mmol) at 25 °C. Cyclization time:
20 h. A cross-coupling reaction was performed according to TP3 using PEPPSI-iPr (41 mg,
2 mol%) and 4-(benzylideneamino)-3-bromobenzonitrile75 (770 mg, 2.70 mmol) at 25 °C within
2 h. The imine hydrolyzed upon acidic workup to give the free amine. Flash column
chromatographical purification on silica gel (pentane/diethyl ether = 2:1) afforded 46d (689 mg,
55%) as a yellow solid.
Mp. : 138.1-139.7. 1H-NMR (CDCl3, 300 MHz): δ = 7.89 (d, J = 8.80 Hz, 1H), 7.50-7.40 (m, 2H), 7.30 (d, J = 2.20
Hz, 1H), 7.052 (dd, J = 8.80 Hz, J = 2.20 Hz, 1H), 6.73 (d, J = 8.44 Hz, 1H), 4.74 (s, 2H), 4.43 (s,
br, 2H) 3.88 (s, 3H), 1.18-0.91 (m, 21H). 13C-NMR (CDCl3, 75 MHz): δ = 157.8, 149.4, 141.3, 136.2, 133.9, 133.8, 133.5, 131.5, 124.1,
119.6, 118.5, 114.8, 114.5, 104.7, 100.0, 58.3, 55.7, 18.0, 12.1.
IR (Diamond ATR, neat): ν~ = 3463 (w), 3460 (w), 3355 (m), 3223 (vw), 2938 (w), 2889 (w),
2885 (w), 2861 (w), 2215 (m), 1631 (m), 1616 (w), 1603 (m), 1576 (w), 1565 (w), 1560 (w), 1540
(w), 1501 (m), 1479 (m), 1470 (w), 1458 (m), 1440 (w), 1424 (w), 1333 (w), 1264 (m), 1238 (m),
1219 (s), 1096 (m), 1076 (w), 1056 (s), 1043 (m), 1020 (m), 1011 (w), 1004 (w), 985 (w), 976 (w),
916 (w), 881 (m), 855 (m), 823 (vs), 801 (s), 775 (w), 734 (w), 686 (w), 677 (w), 670 (w).
MS (EI, 70 eV): m/z = 466 (18) [M+], 423 (29), 393 (100), 293 (24), 262 (12), 75 (11).
HR-MS: (C26H34O2N2SSi) calculated: 466.2110 found: 466.2107.
75 W. F. Bailey, M. W. Carson, J. Org. Chem. 1998, 63, 9960.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
143
((2-(2-Bromo-5-methoxyphenyl)-5-chlorobenzo[b]thiophen-3-yl)methoxy)-triisopropyl-
silane (46e):
The title compound was prepared from the alkynyl(aryl)thioether 43b (1.24 g, 2.00 mmol)
according to TP6 with i-PrMgCl· LiCl (1.86 mL, 1.29 M, 2.4 mmol) at 25 °C. Cyclization time:
24 h. An cross-coupling reaction was performed according to TP3 using Pd(dba)2 (35 mg,
3 mol%), tfp (28 mg, 6 mol%) and 1-bromo-2-iodo-4-methoxybenzene (562 mg, 1.80 mmol) at
25 °C within 5 h. Flash column chromatographical purification on silica gel (pentane/diethyl
ether = 20:1) afforded 46e (729 mg, 75%) as a colorless oil. 1H-NMR (CDCl3, 300 MHz): δ = 8.08 (d, J = 2.15 Hz, 1H), 7.72 (d, J = 8.61 Hz, 1H), 7.54 (d,
J = 9.00 Hz, 1H), 7.32 (dd, J = 8.61 Hz, J = 2.15 Hz, 1H), 6.88 (d, J = 2.93 Hz, 1H), 6.85 (dd,
J = 9.00 Hz, J = 2.93 Hz, 1H), 4.65 (s, 2H), 3.79 (s, 3H), 1.17-1.11 (m, 21H). 13C-NMR (CDCl3, 75 MHz): δ = 158.5, 140.5, 137.6, 135.0, 133.4, 132.9, 130.5, 125.6, 123.7,
122.9, 118.3, 116.7, 116.0, 115.2, 58.9, 55.6, 17.9, 12.0.
IR (Diamond ATR, neat): ν~ = 2941 (m), 2890 (m), 2863 (s), 1590 (m), 1568 (m), 1462 (s),
1442 (m), 1438 (m), 1424 (m), 1389 (m), 1367 (m), 1311 (m), 1288 (s), 1236 (m), 1209 (m), 1172
(m), 1121 (m), 1104 (s), 1078 (vs), 1064 (vs), 1043 (m), 1021 (s), 1005 (m), 996 (m), 881 (s), 851
(m), 800 (s), 733 (m), 682 (s).
MS (EI, 70 eV): m/z = 538 (1) [M+], 497 (100), 367 (23), 311 (29), 288 (88), 271 (30), 251 (14),
208 (22).
HR-MS: (C25H32O2BrClSSi) calculated: 538.0764 found: 538.0762.
4-(Benzylideneamino)-3-(5-chloro-3-(((triisopropylsilyl)oxy)methyl)-benzo[b]thiophen-2-
yl)benzonitrile (46f):
The title compound was prepared from the alkynyl(aryl)thioether 43b (1.24 g, 2.00 mmol)
according to TP6 with i-PrMgCl· LiCl (1.86 mL, 1.29 M, 2.4 mmol) at 25 °C. Cyclization time:
24 h. An cross-coupling reaction was performed according to TP3 using Pd(OAc)2 (9.0 mg,
2 mol%), S-Phos (33 mg, 4 mol%) and 4-(benzylideneamino)-3-bromobenzonitrile75 (514 mg,
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
144
1.80 mmol) at 25 °C within 3 h. Flash column chromatographical purification on silica gel
(pentane/diethyl ether = 3:1, 4% TEA) afforded 46f (848 mg, 84%) as a yellow viscous oil. 1H-NMR (CDCl3, 300 MHz): δ = 8.33 (d, J = 13.7 Hz, 1H), 7.99 (d, J = 2.15 Hz, 1H), 7.87 (dd,
J = 13.7 Hz, J = 2.15 Hz, 1H), 7.78-7.66 (m, 2H), 7.60 (dd, J = 8.22 Hz, J = 1.76 Hz, 1H), 7.57-
7.45 (m, 2H), 7.44-7.39 (m, 1H), 7.28 (dd, J = 8.51 Hz, J = 2.05 Hz, 1H), 7.13 (d, J = 8.22 Hz,
1H), 7.03 (d, J = 8.02 Hz, 1H), 4.81 (s, 2H), 1.14-0.83 (m, 21H). 13C-NMR (CDCl3, 75 MHz): δ = 163.1, 154.8, 140.5, 138.2, 137.0, 136.3, 135.4, 133.6, 133.1,
132.6, 130.4, 129.4, 129.0, 128.3, 125.0, 123.4, 120.3, 118.3, 117.6, 109.0, 58.8, 17.9, 12.0.
IR (Diamond ATR, neat): ν~ = 2941 (m), 2889 (w), 2863 (m), 2225 (m), 1627 (s), 1589 (s),
1576 (s), 1492 (w), 1473 (m), 1451 (m), 1422 (w), 1384 (m), 1373 (w), 1311 (w), 1196 (s), 1169
(m), 1129 (m), 1096 (m), 1078 (s), 1061 (s), 1044 (m), 1012 (m), 999 (m), 994 (m), 978 (m), 880
(s), 821 (s), 802 (s), 757 (s), 731 (m), 688 (vs).
MS (EI, 70 eV): m/z = 558 (16) [M+], 516 (52), 385 (74), 286 (100), 271 (67), 74 (54), 59 (70), 45
(55).
HR-MS: (C32H35ON2ClSSi) calculated: 558.1928 found: 558.1919.
tert-Butyl 3-(((triisopropylsilyl)oxy)methyl)benzo[b]thiophene-5-carboxylate (46g):
The title compound was prepared from the alkynyl(aryl)thioether 43c (1.50 g, 3.00 mmol)
according to TP6 with i-PrMgCl· LiCl (2.44 mL, 1.29 M, 3.15 mmol) at 25 °C. Cyclization time:
52 h. The reaction was quenched with half concentrated aqueous NH4Cl solution, extracted three
times with Et2O, the organic layers dried (MgSO4) and concentrated in vacuo. Flash column
chromatographical purification on silica gel (pentane/diethyl ether = 5:1) afforded 46g (980 mg,
78%) as a colorless oil. 1H-NMR (CDCl3, 300 MHz): δ = 8.40 (d, J = 1.72 Hz, 1H), 7.95 (dd, J = 8.58 Hz, J = 1.72 Hz,
1H), 7.85 (d, J = 8.58 Hz, 1H), 7.41 (s, 1H), 5.08 (s, 2H), 1.62 (s, 9H), 1.26-1.07 (m, 21H). 13C-NMR (CDCl3, 75 MHz): δ = 166.2, 144.9, 137.4, 137.2, 128.0, 124.8, 123.4, 122.8, 122.4,
81.1, 61.0, 28.3, 18.1, 12.0.
IR (Diamond ATR, neat): ν~ = 2956 (m), 2942 (m), 2864 (m), 1711 (s), 1461 (m), 1366 (m),
1319 (w), 1285 (m), 1245 (s), 1164 (s), 1120 (s), 1094 (vs), 1066 (s), 1041 (m), 1014 (m), 995 (m),
881 (s), 850 (m), 806 (m), 793 (m), 758 (vs), 735 (w), 681 (s).
MS (EI, 70 eV): m/z = 420 (1) [M+], 347 (20), 321 (100), 146 (36).
HR-MS: (C23H36O3SSi) calculated: 420.2154 found: 420.2153.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
145
2,2-Dimethyl-1-(3-(((triisopropylsilyl)oxy)methyl)benzo[b]thieno[2,3-d]thiophen-2-yl)-
propan-1-one (46h):
The title compound was prepared from the alkynyl(aryl)thioether 43d (377 mg, 1.00 mmol)
according to TP1 with TMPMgCl· LiCl (1.02 mL, 1.08 M, 1.1 mmol) at 25 °C. The cyclization
was carried out according to TP13 (80 °C, 150 W, 2 h). An acylation reaction was performed
according to TP4 using pivaloyl chloride (109 mg, 0.90 mmol) at 25 °C within 1 h. Flash column
chromatographical purification on silica gel (pentane/diethyl ether = 40:1) afforded 46h (307 mg,
74%) as a light yellow oil. 1H-NMR (CDCl3, 300 MHz): δ = 7.90-7.82 (m, 2H), 7.43-7.36 (m, 2H), 5.29 (s, 2H), 1.45 (s,
9H), 1.21-1-03 (m, 21H). 13C-NMR (CDCl3, 75 MHz): δ = 200.4, 146.1, 145.6, 137.8, 137.1, 131.2, 129.6, 125.8, 124.5,
123.6, 121.1, 64.1, 44.5, 28.2, 18.2, 12.2.
IR (Diamond ATR, neat): ν~ = 2941 (m), 2891 (m), 2888 (m), 2863 (m), 1639 (s), 1462 (m),
1443 (m), 1412 (s), 1394 (m), 1366 (m), 1346 (m), 1316 (m), 1300 (m), 1178 (vs), 1160 (m), 1094
(s), 1069 (s), 1038 (m), 1012 (s), 995 (m), 975 (s), 881 (s), 828 (s), 790 (s), 755 (s), 747 (s), 725 (m),
685 (m), 679 (m).
MS (EI, 70 eV): m/z = 460 (2) [M+], 417 (100), 287 (5), 244 (7), 202 (6), 103 (7), 75 (10), 57 (19),
43 (19).
HR-MS: (C25H36O3S2Si) calculated: 460.1926 found: 460.1918.
Ethyl 3-(((triisopropylsilyl)oxy)methyl)benzo[b]thieno[2,3-d]thiophene-2-carboxylate
(46i):
The title compound was prepared from the alkynyl(aryl)thioether 43d (753 mg, 2.00 mmol)
according to TP1 with TMPMgCl· LiCl (2.04 mL, 1.08 M, 2.2 mmol) at 25 °C. The cyclization
was carried out according to TP13 (80 °C, 150 W, 2 h). Ethyl cyanoformate (178 mg, 1.80 mmol)
was added at -20 °C and the reaction mixture stirred for 2 h while warming to 25 °C. Flash
column chromatographical purification on silica gel (pentane/diethyl ether = 40:1) afforded 46i
(433 mg, 54%) as a light yellow solid.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
146
Mp. : 77.6-79.1 °C. 1H-NMR (CDCl3, 300 MHz): δ = 7.87 (dd, J = 6.10 Hz, J = 3.05 Hz, 2H), 7.39 (dd, J = 6.10
Hz, J = 3.05 Hz, 2H), 5.40 (s, 2H), 4.37 (q, J = 7.12 Hz, 2H), 1.40 (t, J = 7.12 Hz, 3H), 1.35-1.24
(m, 3H), 1.17 (s, 18H). 13C-NMR (CDCl3, 75 MHz): δ = 162.6, 145.0, 144.1, 138.0, 137.9, 131.5, 125.7, 125.0, 124.5,
123.6, 121.4, 62.2, 61.2, 18.1, 14.4, 12.1.
IR (Diamond ATR, neat): ν~ = 2975 (w), 2930 (w), 2871 (w), 1705 (s), 1690 (s), 1598 (w), 1455
(w), 1438 (m), 1391 (w), 1366 (m), 1346 (m), 1318 (m), 1287 (s), 1245 (s), 1157 (vs), 1111 (s),
1088 (s), 1055 (m), 1042 (m), 1007 (m), 902 (m), 848 (m), 834 (m), 800 (m), 788 (w), 756 (vs).
MS (EI, 70 eV): m/z = 448 (3) [M+], 405 (100), 376 (10), 289 (10), 131 (6), 103 (16), 75 (25), 61
(12), 43 (10).
HR-MS: (C23H32O3S2Si) calculated: 448.1562 found: 448.1547.
Ethyl 4-(3-(((triisopropylsilyl)oxy)methyl)benzo[b]thieno[2,3-d]thiophen-2-yl)benzoate
(46j):
The title compound was prepared from the alkynyl(aryl)thioether 43d (753 mg, 2.00 mmol)
according to TP1 with TMPMgCl· LiCl (2.04 mL, 1.08 M, 2.2 mmol) at 25 °C. The cyclization
was carried out according to TP13 (80 °C, 150 W, 2 h). A cross-coupling reaction was performed
according to TP3 using PEPPSI-iPr (27 mg, 2 mol%) and ethyl 4-bromobenzoate (413 mg, 1.80
mmol) at 25 °C within 1 h. Flash column chromatographical purification on silica gel
(pentane/diethyl ether = 30:1) afforded 46j (535 mg, 57%) as a light yellow solid.
Mp. : 71.9-73.9 °C. 1H-NMR (CDCl3, 300 MHz): δ = 8.11 (d, J = 8.10 Hz, 2H), 7.91-7.79 (m, 2H), 7.59 (d, J = 8.10
Hz, 2H), 7.43-7.30 (m, 2H), 4.99 (s, 2H), 4.42 (q, J = 7.25 Hz, 2H), 1.43 (t, J = 7.25 Hz, 3H),
1.26-1.00 (m, 21H). 13C-NMR (CDCl3, 75 MHz): δ = 166.2, 142.6, 139.6, 139.3, 138.6, 133.2, 132.4, 131.9, 129.9,
129.8, 129.4, 128.8, 124.5, 123.7, 120.7, 61.1, 59.9, 18.1, 14.3, 12.0.
IR (Diamond ATR, neat): ν~ = 2940 (m), 2889 (w), 2863 (m), 1718 (s), 1605 (m), 1463 (m),
1445 (m), 1365 (m), 1271 (vs), 1179 (m), 1103 (vs), 1090 (vs), 1074 (s), 1069 (s), 1048 (m), 1015
(m), 1003 (m), 986 (m), 880 (m), 856 (m), 827 (m), 822 (m), 768 (s), 751 (s), 726 (m), 700 (w), 682
(m), 672 (w).
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
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MS (EI, 70 eV): m/z = 525 (4) [M+], 481 (55), 351 (14), 278 (100), 71 (18), 57 (33), 43 (63).
HR-MS: (C29H36O3S2Si) calculated: 524.1875 found: 524.1867.
(4-Chlorophenyl)(3-(((triisopropylsilyl)oxy)methyl)benzo[b]thieno[2,3-d]thiophen-2-
yl)methanone (46k):
The title compound was prepared from the alkynyl(aryl)thioether 43d (753 mg, 2.00 mmol)
according to TP1 with TMPMgCl· LiCl (2.04 mL, 1.08 M, 2.2 mmol) at 25 °C. The cyclization
was carried out according to TP13 (80 °C, 150 W, 2 h). An acylation reaction was performed
according to TP4 using 4-chlorobenzoyl chloride (263 mg, 1.80 mmol) at -40 °C within 3 h while
warming the reaction mixture to 25 °C. Flash column chromatographical purification on silica gel
(pentane/diethyl ether = 40:1) afforded 46k (340 mg, 37%) as a light yellow solid.
Mp. : 96.5-98.6 °C. 1H-NMR (CDCl3, 300 MHz): δ = 7.91-7.86 (m, 2H), 7.86-7.81 (m, 2H), 7.51-7.45 (m, 2H),
7.44-7.38 (m, 2H), 5.40 (s, 2H), 1.37-1.26 (m, 3H), 1.17 (s, 18H). 13C-NMR (CDCl3, 75 MHz): δ = 187.8, 145.8, 145.4, 139.8, 138.6, 137.9, 131.9, 131.2, 130.3,
128.7, 128.6, 126.4, 124.7, 123.8, 121.5, 63.2, 18.1, 12.1.
IR (Diamond ATR, neat): ν~ = 2938 (w), 2861 (w), 2360 (w), 2339 (w), 1717 (w), 1623 (m),
1616 (m), 1593 (w), 1471 (w), 1464 (w), 1456 (w), 1446 (w), 1436 (w), 1415 (m), 1394 (w), 1387
(w), 1373 (m), 1365 (m), 1349 (m), 1319 (m), 1304 (m), 1280 (w), 1263 (m), 1217 (w), 1175 (w),
1088 (s), 1072 (m), 1069 (m), 1064 (m), 1020 (w), 1014 (m), 994 (m), 970 (w), 950 (m), 878 (m),
842 (m), 828 (m), 800 (s), 754 (vs), 727 (m), 679 (w).
MS (EI, 70 eV): m/z = 514 (1) [M+], 471 (100), 277 (14), 139 (13), 74 (5), 59 (8), 45 (6).
HR-MS: (C27H31O2ClS2Si) calculated: 514.1223 found: 514.1217.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
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Diversification of Polyfunctional Benzothiophenes to new Heterocyclic Scaffolds
(2-(2-Bromophenyl)-6-methoxybenzo[b]thiophen-3-yl)methanol (47a):
The title compound was prepared according to TP14 from 46c (759 mg, 1.50 mmol) and TBAF
trihydrate (710 mg, 2.25 mmol) in 1 h. Flash column chromatographical purification on silica gel
(pentane/diethyl ether = 1:1) afforded 47a (460 mg, 88%) as a pale yellow solid.
Mp. : 106.7-109.1 °C. 1H-NMR (CDCl3, 300 MHz): δ = 7.89 (d, J = 8.77 Hz, 1H), 7.69 (dd, J = 7.63 Hz, J = 1.12 Hz,
1H), 7.46-7.41 (m, 1H), 7.40-7.35 (m, 1H), 7.32 (d, J = 2.29 Hz, 1H), 7.31-7.27 (m, 1H), 7.07 (dd,
J = 8.77 Hz, J = 2.29 Hz, 1H), 4.63 (s, 2H), 3.88 (s, 3H), 1.73 (s, br, 1H). 13C-NMR (CDCl3, 75 MHz): δ = 157.8, 141.1, 137.1, 134.5, 132.9, 132.8, 132.4, 130.2, 127.2,
124.9, 123.7, 123.6, 114.5, 104.7, 57.8, 55.6.
IR (Diamond ATR, neat): ν~ = 3386 (w), 2935 (w), 2832 (w), 2360 (vw), 1601 (m), 1590 (m),
1540 (w), 1476 (m), 1463 (s), 1438 (m), 1422 (m), 1350 (w), 1317 (w), 1264 (m), 1247 (m), 1231
(s), 1209 (m), 1090 (w), 1046 (s), 1034 (vs), 1021 (s), 982 (m), 931 (m), 881 (m), 832 (s), 814 (m),
793 (m), 752 (vs), 744 (m), 705 (w), 679 (m).
MS (EI, 70 eV): m/z = 348 (100) [M+], 331 (30), 267 (38), 225 (24), 208 (24), 195 (25), 165 (29),
152 (23), 74 (39), 59 (50), 45 (40).
HR-MS: (C16H13O2BrS) calculated: 347.9820 found: 347.9814.
(2-(2-Bromo-5-methoxyphenyl)-5-chlorobenzo[b]thiophen-3-yl)methanol (47b):
The title compound was prepared according to TP14 from 46e (540 mg, 1.00 mmol) and TBAF
trihydrate (473 mg, 1.50 mmol) in 1 h. Flash column chromatographical purification on silica gel
(pentane/diethyl ether = 2:1) afforded 47b (345 mg, 90%) as a pale yellow solid.
Mp. : 145.8-147.2 °C. 1H-NMR (CDCl3, 300 MHz): δ = 8.02 (d, J = 1.94 Hz, 1H), 7.74 (d, J = 8.57 Hz, 1H), 7.56 (d, J
= 8.85 Hz, 1H), 7.35 (dd, J = 8.57 Hz, J = 1.94 Hz, 1H), 6.98 (d, J = 3.04 Hz, 1H), 6.87 (dd, J =
8.85 Hz, J = 3.04 Hz, 1H), 4.66 (s, 2H), 3.80 (s, 3H), 1.74 (s, br, 1H).
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
149
13C-NMR (CDCl3, 75 MHz): δ = 158.6, 141.5, 140.0, 137.7, 134.7, 133.6, 132.3, 131.0, 125.3,
123.2, 122.8, 117.9, 116.7, 114.8, 57.6, 55.6.
IR (Diamond ATR, neat): ν~ = 3347 (w), 2933 (w), 2833 (w), 1590 (m), 1567 (m), 1463 (s),
1436 (s), 1422 (s), 1309 (m), 1284 (s), 1260 (w), 1252 (w), 1237 (s), 1200 (m), 1171 (s), 1147 (m),
1122 (w), 1099 (m), 1077 (s), 1057 (m), 1043 (s), 1017 (vs), 982 (m), 958 (s), 873 (m), 858 (m), 817
(s), 798 (vs), 750 (m).
MS (EI, 70 eV): m/z = 382 (45) [M+], 303 (100), 285 (31), 271 (22), 240 (40), 208 (32), 195 (32),
74 (18), 59 (28), 45 (23).
HR-MS: (C16H12O2BrClS) calculated: 381.9430 found: 381.9420.
(4-Fluorophenyl)(3-(hydroxymethyl)-6-methoxybenzo[b]thiophen-2-yl)methanone (47c):
The title compound was prepared according to TP14 from 46b (641 mg, 1.50 mmol) and TBAF
trihydrate (710 mg, 2.25 mmol) in 1 h. Flash column chromatographical purification on silica gel
(pentane/diethyl ether = 1:1) afforded 47c (391 mg, 82%) as a yellow solid.
Mp. : 128.8-130.6 °C. 1H-NMR (DMSO-d6, 400 MHz): δ = 8.07 (d, J = 9.00 Hz, 1H), 7.93-7.87 (m, 2H), 7.59 (d, J =
2.35 Hz, 1H), 7.42-7.33 (m, 2H), 7.11 (dd, J = 9.00 Hz, J = 2.35 Hz, 1H), 5.23 (s, br, 1H), 4.69 (s,
2H), 3.85 (s, 3H). 13C-NMR (DMSO-d6, 100 MHz): δ = 188.6, 163.5 (d, J = 251 Hz), 159.2, 142.1, 142.1, 135.4
(d, J = 3.02 Hz), 133.4, 133.1, 132.0 (d, J = 9.54 Hz), 126.3, 115.7, 115.5, 104.5, 55.9, 55.6.
IR (Diamond ATR, neat): ν~ = 3069 (w), 2971 (w), 2841 (w), 1621 (m), 1616 (m), 1595 (s),
1489 (s), 1462 (m), 1456 (m), 1418 (w), 1405 (m), 1359 (m), 1341 (m), 1298 (w), 1269 (s), 1223
(vs), 1182 (m), 1152 (s), 1097 (w), 1038 (s), 1029 (s), 1011 (m), 1002 (m), 981 (s), 918 (m), 882
(w), 848 (s), 828 (m), 815 (m), 771 (w), 760 (s), 661 (w).
MS (EI, 70 eV): m/z = 316 (100) [M+], 298 (66), 255 (53), 226 (33), 123 (70), 95 (60), 43 (100).
HR-MS: (C17H13O3FS) calculated: 316.0569 found: 316.0556.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
150
9-Methoxy-6H-benzo[4,5]thieno[3,2-c]chromene (48a):
The alcohol 47a (274 mg, 0.78 mmol) was dissolved in THF (2.0 mL), NaH (28.1 mg, 1.50
mmol) was added at 25 °C and the mixture stirred at that temperature for 2 h. Then dry DMF
(2.0 mL) was added and the cyclization was carried out according to TP13 (75 °C, 125 W, 2 h).
The reaction was quenched with half concentrated aqueous NH4Cl solution, extracted three times
with Et2O, the organic layers dried (MgSO4) and concentrated in vacuo. Flash column
chromatographical purification on silica gel (pentane/diethyl ether = 5:1) afforded the title
compound 48a (207 mg, 77%) as a white powder.
Mp. : 141.8-143.1 °C. 1H-NMR (CDCl3, 300 MHz): δ = 7.39 (d, J = 8.80 Hz, 1H), 7.32 (d, J = 2.20 Hz, 1H), 7.33-
7.27 (m, 1H), 7.23-7.16 (m, 1H), 6.99 (dd, J = 8.80 Hz, J = 2.20 Hz, 1H), 7.01-6.93 (m, 2H), 5.47
(s, 2H), 3.87 (s, 3H). 13C-NMR (CDCl3, 75 MHz): δ = 157.7, 152.6, 141.1, 130.6, 129.9, 129.0, 124.8, 123.5, 121.8,
121.3, 120.2, 116.2, 114.4, 105.9, 65.6, 55.6.
IR (Diamond ATR, neat): ν~ = 2853 (vw), 1736 (V(w)), 1605 (w), 1599 (w), 1580 (w), 1534
(w), 1486 (w), 1475 (m), 1461 (w), 1457 (w), 1451 (m), 1437 (m), 1419 (w), 1407 (w), 1387 (w),
1342 (w), 1294 (w), 1266 (s), 1227 (m), 1207 (m), 1186 (w), 1155 (w), 1131 (w), 1117 (w), 1043
(m), 1034 (m), 1020 (m), 995 (m), 966 (w), 886 (w), 839 (w), 833 (m), 816 (s), 791 (m), 753 (vs),
740 (w), 727 (w), 658 (w).
MS (EI, 70 eV): m/z = 268 (100) [M+], 253 (33), 224 (28), 195 (11), 71 (17), 59 (25), 43 (55).
HR-MS: (C16H12O2S) calculated: 268.0558 found: 268.0556.
8-Chloro-2-methoxy-6H-benzo[4,5]thieno[3,2-c]chromene (48b):
The alcohol 47b (250 mg, 0.65 mmol) was dissolved in THF (2.0 mL), NaH (30.0 mg,
1.20 mmol) was added at 25 °C and the mixture stirred at that temperature for 2 h. Then dry
DMF (2.0 mL) was added and the cyclization was carried out according to TP13 (75 °C, 125 W,
2 h). The reaction was quenched with half concentrated aqueous NH4Cl solution, extracted three
times with Et2O, the organic layers dried (MgSO4) and concentrated in vacuo. Flash column
chromatographical purification on silica gel (pentane/diethyl ether = 5:1) afforded the title
compound 48b (156 mg, 79%) as a white powder.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
151
Mp. : 187.6-189.2 °C. 1H-NMR (Acetone-d6/DMSO-d6, 300 MHz): δ = 8.05 (d, J = 8.61 Hz, 1H), 7.88 (d, J = 2.15
Hz, 1H), 7.39 (dd, J = 8.61 Hz, J = 2.15 Hz, 1H), 6.94 (d, J = 8.71 Hz, 1H), 6.92 (d, J = 2.74 Hz,
1H), 6.85 (dd, J = 8.71 Hz, J = 2.74 Hz, 1H), 5.49 (s, 2H), 3.79 (s, 3H). 13C-NMR (Acetone-d6/DMSO-d6, 75 MHz): δ = 155.2, 147.5, 138.4, 138.1, 131.1, 126.5,
125.6, 125.2, 121.8, 120.6, 117.9, 116.3, 112.2, 109.4, 65.3, 56.1.
IR (Diamond ATR, neat): ν~ = 2360 (s), 2344 (m), 2341 (m), 1734 (m), 1558 (m), 1490 (m),
1476 (w), 1472 (w), 1464 (w), 1452 (m), 1447 (m), 1444 (m), 1312 (m), 1265 (w), 1217 (m), 1201
(vs), 1175 (m), 1076 (m), 1046 (vs), 1004 (m), 851 (s), 806 (s), 796 (vs), 723 (m).
MS (EI, 70 eV): m/z = 302 (98) [M+], 195 (17), 84 (38), 74 (68), 59 (100), 45 (63).
HR-MS: (C16H11O2ClS) calculated: 302.0168 found: 302.0157.
4-(4-Fluorophenyl)-7-methoxybenzo[4,5]thieno[2,3-d]pyridazine (48c):
The alcohol 47c (200 mg, 0.63 mmol) was dissolved in CH2Cl2 (5.0 mL), Dess-Martin
periodinane (536 mg, 1.26 mmol) was added at 0 °C and the mixture stirred for 12 h while
warming to 25 °C. The reaction was quenched with half concentrated aqueous Na2S2O3 solution,
extracted three times with CH2Cl2, the organic layers dried (MgSO4) and concentrated in vacuo.
The crude product was dissolved in EtOH (5.0 mL), hydrazine hydrate (100 mg, 2.00 mmol, 64%
hydrazine content) was added at 25 °C and the resulting suspension stirred for 12 h. The reaction
was quenched with half concentrated aqueous NH4Cl solution, extracted three times with Et2O,
the organic layers dried (MgSO4) and concentrated in vacuo. Flash column chromatographical
purification on silica gel (diethyl ether) afforded the title compound 48c (159 mg, 81%) as a
yellow powder.
Mp. : 202.6-204.0 °C. 1H-NMR (CDCl3, 300 MHz): δ = 9.64 (s, 1H), 8.17 (d, J = 8.85 Hz, 1H), 8.15-8.05 (m, 2H),
7.37 (d, J = 2.25 Hz, 1H), 7.31-7.20 (m, 2H), 7.16 (dd, J = 8.85 Hz, J = 2.25 Hz, 1H), 3.91 (s,
3H). 13C-NMR (CDCl3, 75 MHz): δ = 164.0 (d, J = 251 Hz), 161.4, 154.5, 142.9, 142.1, 137.2, 133.7,
132.9 (d, J = 3.02 Hz), 130.4 (d, J = 9.06 Hz), 125.5, 123.9, 116.1 (d, J = 21.9 Hz), 115.7, 105.5,
55.8.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS BENZO[b]THIOPHENES
152
IR (Diamond ATR, neat): ν~ = 2926 (w), 2840 (w), 2360 (w), 1734 (w), 1596 (s), 1500 (s), 1478
(m), 1456 (m), 1437 (m), 1429 (m), 1381 (m), 1372 (m), 1348 (m), 1332 (m), 1313 (m), 1264 (m),
1231 (vs), 1223 (s), 1198 (m), 1185 (m), 1154 (m), 1132 (m), 1096 (m), 1042 (s), 1020 (m), 1014
(m), 995 (m), 884 (m), 865 (s), 845 (s), 817 (s), 798 (s), 771 (m), 765 (m).
MS (EI, 70 eV): m/z = 310 (100) [M+], 295 (28), 267 (31), 239 (50), 207 (13), 74 (11), 49 (12).
HR-MS: (C17H11ON2FS) calculated: 310.0576 found: 310.0567.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS SOLID ZINC REAGENTS
153
3.3 Preparation and Reactions of Solid Functionalized Organozinc Reagents
Preparation of Organozinc-Reagents
(4-Methoxyphenyl)zinc pivalate (18a)
a) Magnesium insertion in the presence of 1.0 equiv. of Zn(OPiv)2· 2 LiCl
According to TP16 Zn(OPiv)2· 2 LiCl (3.52 g, 10.0 mmol) and 4-bromoanisole (1.87 g,
10.0 mmol) were dissolved in 20 mL of dry THF. Magnesium turnings (608 mg, 25.0 mmol) were
added and the reaction mixture was stirred for 2 h at 22 °C. After subsequent cannulation to
another argon-flushed Schlenk-flask the solvent was removed in vacuo. (4-Methoxyphenyl)zinc
pivalate (18a) was obtained as a grey solid (5.85 g). The content of active zinc species was
determined by titration of 199 mg of the reagent with a stock solution of iodine (1.0 M in THF).
A concentration of 865 mg/mmol was determined which corresponds to a yield of 78%.
b) Magnesium insertion in the presence of 1.5 equiv. of Zn(OPiv)2· 2 LiCl
According to TP16 Zn(OPiv)2· 2 LiCl (3.97 g, 11.3 mmol) and 4-bromoanisole (1.40 g,
7.50 mmol) were dissolved in 20 mL of dry THF. Magnesium turnings (456 mg, 18.8 mmol) were
added and the reaction mixture was stirred for 2 h at 22 °C. After subsequent cannulation to
another argon-flushed Schlenk-flask the solvent was removed in vacuo. (4-Methoxyphenyl)zinc
pivalate (18a) was obtained as a grey solid (5.16 g). The content of active zinc species was
determined by titration of 337 mg of the reagent with a stock solution of iodine (1.0 M in THF).
A concentration of 936 mg/mmol was determined which corresponds to a yield of 74%.
(4-(Methylthio)phenyl)zinc pivalate (18b)
According to TP16 Zn(OPiv)2· 2 LiCl (3.52 g, 10.0 mmol) and 4-bromothioanisole (1.02 g,
5.00 mmol) were dissolved in 15 mL of dry THF. Magnesium turnings (304 mg, 12.5 mmol) were
added and the reaction mixture was stirred for 2 h at 22 °C. After subsequent cannulation to
another argon-flushed Schlenk-flask the solvent was removed in vacuo. (4-Thiomethylphenyl)zinc
pivalate (18b) was obtained as a orange solid (3.49 g). The content of active zinc species was
determined by titration of 190 mg of the reagent with a stock solution of iodine (1.0 M in THF).
A concentration of 904 mg/mmol was determined which corresponds to a yield of 77%.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS SOLID ZINC REAGENTS
154
(4-(Trimethylsilyl)phenyl)zinc pivalate (18c)
According to TP16 Zn(OPiv)2· 2 LiCl (2.64 g, 7.50 mmol) and (4-bromophenyl)(trimethyl)silane
(1.15 g, 5.00 mmol) were dissolved in 15 mL of dry THF. Magnesium turnings (304 mg,
12.5 mmol) were added and the reaction mixture was stirred for 2 h at 22 °C. After subsequent
cannulation to another argon-flushed Schlenk-flask the solvent was removed in vacuo. (4-
(Trimethylsilyl)phenyl)zinc pivalate (18c) was obtained as a grey solid (4.03 g). The content of
active zinc species was determined by titration of 270 mg of the reagent with a stock solution of
iodine (1.0 M in THF). A concentration of 1000 mg/mmol was determined which corresponds to
a yield of 81%.
(4-Fluorophenyl)zinc pivalate (18d)
According to TP16 Zn(OPiv)2· 2 LiCl (2.64 g, 7.50 mmol) and 1-bromo-4-fluorobenzene
(875 mg, 5.00 mmol) were dissolved in 15 mL of dry THF. Magnesium turnings (304 mg,
12.5 mmol) were added and the reaction mixture was stirred for 2 h at 22 °C. After subsequent
cannulation to another argon-flushed Schlenk-flask the solvent was removed in vacuo. (4-
Fluorophenyl)zinc pivalate (18d) was obtained as a grey solid (3.34 g). The content of active zinc
species was determined by titration of 171 mg of the reagent with a stock solution of iodine
(1.0 M in THF). A concentration of 950 mg/mmol was determined which corresponds to a yield
of 70%.
(4-(Ethoxycarbonyl)phenyl)zinc pivalate (18e)
a) Magnesium insertion in the presence of Zn(OPiv)2· 2 LiCl
According to TP16 Zn(OPiv)2· 2 LiCl (2.64 g, 7.50 mmol) and ethyl 4-bromobenzoate (1.15 g,
5.00 mmol) were dissolved in 15 mL of dry THF. Magnesium turnings (304 mg, 12.5 mmol) were
added and the reaction mixture was stirred for 2 h at 22 °C. After subsequent cannulation to
another argon-flushed Schlenk-flask the solvent was removed in vacuo. (4-
(Ethoxycarbonyl)phenyl)zinc pivalate (18e) was obtained as a yellowish solid (4.01 g). The
content of active zinc species was determined by titration of 283 mg of the reagent with a stock
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS SOLID ZINC REAGENTS
155
solution of iodine (1.0 M in THF). A concentration of 1348 mg/mmol was determined which
corresponds to a yield of 59%.
b) Halogen-magnesium exchange and subsequent transmetalation with Zn(OPiv)2· 2 LiCl
According to TP17 ethyl 4-iodobenzoate (1.38 g, 5.00 mmol) was dissolved in 2.5 mL of dry
THF and the mixture was cooled to -30 °C. i-PrMgCl· LiCl (4.74 mL, 1.16 M in THF, 5.50 mmol)
was added dropwise and the mixture was stirred for 30 min at -30 °C. A solution of
Zn(OPiv)2· 2 LiCl (2.64 g, 7.50 mmol) in 15 mL of dry THF was added dropwise and the mixture
was stirred at -30°C for 30 min and then slowly warmed to room temperature. The solvent was
removed in vacuo and (4-(ethoxycarbonyl)phenyl)zinc pivalate (18e) was obtained as a yellowish
solid (4.56 g). The content of active zinc species was determined by titration of 277 mg of the
reagent with a stock solution of iodine (1.0 M in THF). A concentration of 1259 mg/mmol was
determined which corresponds to a yield of 72%.
(4-Cyanophenyl)zinc pivalate (18f)
a) Magnesium insertion in the presence of Zn(OPiv)2· 2 LiCl
According to TP16 Zn(OPiv)2· 2 LiCl (2.64 g, 7.50 mmol) and 4-bromobenzonitrile (910 mg,
5.00 mmol) were dissolved in 15 mL of dry THF. Magnesium turnings (304 mg, 12.5 mmol) were
added and the reaction mixture was stirred for 2 h at 22 °C. After subsequent cannulation to
another argon-flushed Schlenk-flask the solvent was removed in vacuo. (4-Cyanophenyl)zinc
pivalate (18f) was obtained as a yellowish solid (3.68 g). The content of active zinc species was
determined by titration of 196 mg of the reagent with a stock solution of iodine (1.0 M in THF).
A concentration of 1153 mg/mmol was determined which corresponds to a yield of 64%.
b) Halogen-Magnesium exchange and subsequent transmetalation with Zn(OPiv)2· 2 LiCl
According to TP17 4-bromobenzonitrile (910 mg, 5.00 mmol) was dissolved in 7.0 mL of dry
THF and the mixture was cooled to 0 °C. i-PrMgCl· LiCl (4.52 mL, 1.16 M in THF, 5.25 mmol)
was added dropwise and the mixture was stirred for 2 h at 0 °C. A solution of Zn(OPiv)2· 2 LiCl
(2.64 g, 7.50 mmol) in 15 mL of dry THF was added dropwise and the mixture was stirred at 0°C
for 30 min and then slowly warmed to room temperature. The solvent was removed in vacuo and
(4-cyanophenyl)zinc pivalate (18f) was obtained as a colourless solid (4.11 g). The content of
active zinc species was determined by titration of 279 mg of the reagent with a stock solution of
iodine (1.0 M in THF). A concentration of 930 mg/mmol was determined which corresponds to
a yield of 89%.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS SOLID ZINC REAGENTS
156
(3-(Trifluoromethyl)benzyl)zinc pivalate (18g)
According to TP16 Zn(OPiv)2· 2 LiCl (2.64 g, 7.50 mmol) and 1-(chloromethyl)-3-
(trifluoromethyl)benzene (973 mg, 5.00 mmol) were dissolved in 15 mL of dry THF. Magnesium
turnings (304 mg, 12.5 mmol) were added and the reaction mixture was stirred for 2 h at 22 °C.
After subsequent cannulation to another argon-flushed Schlenk-flask the solvent was removed in
vacuo. (3-(Trifluoromethyl)benzyl)zinc pivalate (18g) was obtained as a grey solid (3.61 g). The
content of active zinc species was determined by titration of 108 mg of the reagent with a stock
solution of iodine (1.0 M in THF). A concentration of 1080 mg/mmol was determined which
corresponds to a yield of 67%.
(3-Methoxybenzyl)zinc pivalate (18h)
According to TP16 Zn(OPiv)2· 2 LiCl (2.64 g, 7.50 mmol) and 1-(chloromethyl)-3-
methoxybenzene (783 mg, 5.00 mmol) were dissolved in 15 mL of dry THF. Magnesium turnings
(304 mg, 12.5 mmol) were added and the reaction mixture was stirred for 2 h at 22 °C. After
subsequent cannulation to another argon-flushed Schlenk-flask the solvent was removed in vacuo.
(3-Methoxybenzyl)zinc pivalate (18h) was obtained as a grey solid (3.02 g). The content of active
zinc species was determined by titration of 260 mg of the reagent with a stock solution of iodine
(1.0 M in THF). A concentration of 897 mg/mmol was determined which corresponds to a yield
of 67%.
(2,4-Dimethoxypyrimidin-5-yl)zinc pivalate (18i)
According to TP16 Zn(OPiv)2· 2 LiCl (2.64 g, 7.50 mmol) and 5-bromo-2,4-
dimethoxypyrimidine (1.10 g, 5.00 mmol) were dissolved in 15 mL of dry THF. Magnesium
turnings (304 mg, 12.5 mmol) were added and the reaction mixture was stirred for 2 h at 22 °C.
After subsequent cannulation to another argon-flushed Schlenk-flask the solvent was removed in
vacuo. (2,4-Dimethoxypyrimidin-5-yl)zinc pivalate (18i) was obtained as a yellow solid (3.62 g).
The content of active zinc species was determined by titration of 181 mg of the reagent with a
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS SOLID ZINC REAGENTS
157
stock solution of iodine (1.0 M in THF). A concentration of 1131 mg/mmol was determined
which corresponds to a yield of 65%.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS SOLID ZINC REAGENTS
158
Preparation of Cross-Coupling Products
Methyl 4'-cyano-[1,1'-biphenyl]-4-carboxylate (19a)
According to TP18 (4-cyanophenyl)zinc pivalate (18f; 1.48 g, 900 mg/mmol, 1.64 mmol) was
dissolved in dry THF (4.0 mL). Methyl 4-bromobenzoate (296 mg, 1.38 mmol) and PEPPSI-iPr
(22 mg, 0.03 mmol) were added and the mixture was stirred for 2 h at 25 °C. Purification by flash
chromatography (pentane/diethyl ether = 3:1) afforded the biphenyl 19a (265 mg, 81%) as white
solid.
Mp. : 142.8-144.6 °C. 1H-NMR (300 MHz, CDCl3): δ = 8.13 (d, J = 8.3 Hz, 2H), 7.76-7.69 (m, 4H), 7.65 (d, J = 8.3
Hz, 2H), 3.94 (s, 3H). 13C-NMR (75 MHz, CDCl3): δ = 166.6, 144.4, 143.4, 132.7, 130.3, 130.2, 127.9, 127.2, 118.6,
111.8, 52.3.
IR (Diamond ATR, neat): ν~ = 2960 (w), 2925 (w), 2866 (w), 2225 (m), 1722 (s), 1693 (m),
1681 (m), 1605 (m), 1430 (m), 1394 (m), 1279 (vs), 1208 (m), 1182 (m), 1103 (s), 1020 (w), 958
(w), 864 (w), 830 (s), 768 (s), 736 (m), 726 (m), 696 (m).
MS (EI, 70 eV): m/z (%) = 237 (M+, 43), 206 (100), 178 (22), 151 (21), 103 (4), 89 (4), 76 (5).
HRMS (C15H10O2N): calculated: 237.0790 found: 237.0776.
(4'-(Methylthio)-[1,1'-biphenyl]-2-yl)(morpholino)methanone (19b)
According to TP18 (4-(methylthio)phenyl)zinc pivalate (18b; 574 mg, 904 mg/mmol, 0.63 mmol)
was dissolved in dry THF (3.0 mL). (2-Bromophenyl)(morpholino)methanone (144 mg,
0.53 mmol) and PEPPSI-iPr (9 mg, 0.01 mmol) were added and the mixture was stirred for 2 h at
25 °C. Purification by flash chromatography (diethyl ether) afforded the product 19b (147 mg,
88%) as a colorless oil. 1H-NMR (300 MHz, CDCl3): δ = 7.44-7.36 (m, 6H), 7.30-7.26 (m, 2H), 3.67-3.45 (m, 3H),
3.32-3.20 (m, 2H), 3.00-2.90 (m, 1H), 2.77-2.58 (m, 2H), 2.49 (s, 3H). 13C-NMR (75 MHz, CDCl3): δ = 169.9, 138.7, 137.8, 136.2, 134.6, 129.6, 129.1, 129.0, 127.8,
127.7, 126.3, 66.2, 66.1, 46.7, 41.7, 15.6.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS SOLID ZINC REAGENTS
159
IR (Diamond ATR, neat): ν~ = 2967 (w), 2964 (w), 2919 (w), 2853 (w), 1625 (vs), 1599 (m),
1571 (w), 1500 (w), 1477 (m), 1455 (m), 1442 (m), 1425 (s), 1401 (m), 1389 (w), 1360 (w), 1299
(m), 1279 (s), 1261 (m), 1241 (m), 1156 (w), 1110 (vs), 1091 (m), 1067 (m), 1050 (w), 1018 (s),
1010 (s), 968 (w), 955 (w), 935 (w), 895 (w), 841 (m), 825 (m), 779 (m), 760 (s), 738 (m), 715 (w).
MS (EI, 70 eV): m/z (%) = 313 (M+, 68), 227 (100), 184 (14), 180 (50), 152 (28), 86 (10).
HRMS (C18H19O2NS): calculated: 313.1136 found: 313.1131.
Morpholino(4'-(trimethylsilyl)-[1,1'-biphenyl]-2-yl)methanone (19c)
According to TP18 (4-(trimethylsilyl)phenyl)zinc pivalate (18c; 480 mg, 1030 mg/mmol,
0.47 mmol) was dissolved in dry THF (3.0 mL). (2-bromophenyl)(morpholino)methanone
(107 mg, 0.40 mmol) and PEPPSI-iPr (6 mg, 0.01 mmol) were added and the mixture was stirred
for 2 h at 50 °C. Purification by flash chromatography (diethyl ether) afforded the product 19c
(109 mg, 80%) as a colorless oil. 1H-NMR (300 MHz, CDCl3): δ = 7.57 (d, J = 8.2 Hz, 2H), 7.47-7.39 (m, 6H), 3.73-3.67 (m,
1H), 3.61-3.55 (m, 1H), 3.44-3.39 (m, 1H), 3.27-3.21 (m, 1H), 3.21-3.16 (m, 1H), 2.98-2.91 (m,
1H), 2.75-2.69 (m, 1H), 2.44-2.37 (m, 1H), 0.3 (s, 9H). 13C-NMR (75 MHz, CDCl3): δ = 169.9, 140.3, 139.9, 138.6, 134.8, 133.5, 129.6, 129.2, 128.0,
127.9, 127.7, 66.0, 65.9, 46.7, 41.8, -1.2.
IR (Diamond ATR, neat): ν~ = 2955 (w), 2898 (w), 2854 (w), 1629 (s), 1597 (m), 1479 (w),
1457 (m), 1445 (m), 1426 (m), 1386 (w), 1361 (w), 1299 (w), 1279 (m), 1271 (m), 1247 (s), 1155
(w), 1111 (s), 1068 (w), 1020 (m), 1010 (m), 1004 (m), 838 (vs), 825 (vs), 779 (m), 750 (vs), 719
(m), 708 (m), 693 (w), 658 (m)
MS (EI, 70 eV): m/z (%) = 229 (M+, 20), 253 (40), 239 (12), 165 (13), 144 (22), 86 (29), 73
(100).
HRMS (C20H25O2NSi): calculated: 339.1655 found: 339.1646.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS SOLID ZINC REAGENTS
160
6-Amino-4'-fluoro-[1,1'-biphenyl]-3-carbonitrile (19d)
According to TP18 (4-fluorophenyl)zinc pivalate (18d; 690 mg, 950 mg/mmol, 0.73 mmol) was
dissolved in dry THF (3.0 mL). 4-amino-3-bromobenzonitrile (121 mg, 0.61 mmol) and PEPPSI-
iPr (10 mg, 0.015 mmol) were added and the mixture was stirred for 2 h at 25 °C. Purification by
flash chromatography (pentane/ethyl acetate = 4:1) afforded the biphenyl 19d (142 mg, 79%) as
pale yellow solid.
Mp. : 157.8-159.7 °C. 1H-NMR (300 MHz, CDCl3): δ = 7.42-7.33 (m, 4H), 7.15 (t, J = 8.4 Hz, 2H), 6.74 (d, J = 8.3
Hz 1H), 4.14 (s, br, 2H). 13C-NMR (75 MHz, CDCl3): δ = 164.1 (d, J = 248.0 Hz), 147.6, 134.4, 133.0 (d, J = 3.7 Hz),
132.7, 130.6 (d, J = 8.1 Hz), 126.4, 119.8, 116.2 (d, J = 21.6 Hz), 115.2, 100.7.
IR (Diamond ATR, neat): ν~ = 3472 (m), 3363 (m), 2215 (s), 1631 (s), 1600 (s), 1571 (m), 1507
(s), 1496 (vs), 1427 (w), 1395 (m), 1320 (m), 1299 (w), 1210 (s), 1190 (w), 1157 (s), 1096 (w), 906
(w), 840 (s), 824 (s), 815 (s), 808 (s), 764 (m).
MS (EI, 70 eV): m/z (%) = 212 (M+, 100), 192 (10), 184 (9), 157 (5), 92 (6).
HRMS (C13H9N2F): calculated: 212.0750 found: 212.0736.
Diethyl 6-amino-[1,1'-biphenyl]-3,4'-dicarboxylate (19e)
According to TP18 (4-(ethoxycarbonyl)phenyl)zinc pivalate (18e; 980 mg, 1200 mg/mmol,
0.81 mmol) was dissolved in dry THF (3.0 mL). Ethyl 4-amino-3-bromobenzoate (167 mg,
0.69 mmol) and PEPPSI-iPr (28 mg, 0.03 mmol) were added and the mixture was stirred for 2 h
at 25 °C. Purification by flash chromatography (pentane/diethyl ether = 2:1) afforded the
biphenyl 19e (149 mg, 69%) as colorless oil. 1H-NMR (300 MHz, CDCl3): δ = 8.12 (d, J = 8.1 Hz, 2H), 8.12 (dd, J = 8.1 Hz, J = 1.8 Hz,
1H), 7.82 (d, J = 1.8 Hz, 1H), 7.52 (d, J = 8.4 Hz, 2H), 6.75 (d, J = 8.4 Hz, 2H), 4.40 (t,
J = 7.1 Hz, 2H), 4.32 (t, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H). 13C-NMR (75 MHz, CDCl3): δ = 166.5, 166.3, 147.4, 143.1, 132.2, 131.0, 130.2, 129.7, 129.0,
125.5, 120.5, 114.9, 61.1, 60.5, 14.4, 14.3.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS SOLID ZINC REAGENTS
161
IR (Diamond ATR, neat): ν~ = 3434 (w), 3350 (w), 1706 (s), 1672 (s), 1624 (m), 1601 (s), 1510
(m), 1461 (w), 1445 (w), 1432 (w), 1366 (m), 1340 (w), 1309 (m), 1292 (s), 1270 (s), 1240 (vs),
1179 (m), 1173 (m), 1162 (m), 1099 (vs), 1050 (w), 1036 (m), 1011 (m), 977 (w), 964 (w), 955 (w),
923 (w), 895 (w), 860 (m), 830 (m), 771 (s), 731 (s), 707 (m)
MS (EI, 70 eV): m/z (%) = 313 (M+, 100), 285 (17), 268 (59), 240 (18), 167 (15).
HRMS (C18H19O4N): calculated: 313.1314 found: 313.1305.
Ethyl 4-amino-3-(3-(trifluoromethyl)benzyl)benzoate (19f)
According to TP18 (3-(trifluoromethyl)benzyl)zinc pivalate (18g; 915 mg, 1080 mg/mmol,
0.85 mmol) was dissolved in dry THF (3.0 mL). Ethyl 4-amino-3-bromobenzoate (174 mg,
0.71 mmol) and PEPPSI-iPr (12 mg, 0.02 mmol) were added and the mixture was stirred for 3 h
at 25 °C. Purification by flash chromatography (pentane/ethyl acetate = 4:1) afforded the
biphenyl 19f (151 mg, 66%) as a colorless oil. 1H-NMR (300 MHz, CDCl3): δ = 7.95-7.70 (m, 2H), 7.60-7.28 (m, 4H), 6.66 (d, J = 8.3 Hz,
1H), 4.32 (q, J = 8.0 Hz, 2H), 3.97 (s, 2H), 3.80-3.20 (s, br, 2H) 1.36 (7, J = 8.0 Hz, 3H). 13C-NMR (75 MHz, CDCl3): δ = 166.7, 148.9, 139.6, 132.9, 131.6, 131.1 (q, J = 31.5 Hz), 130.3,
129.8 (q, J = 40.5 Hz), 129.2, 125.0 (q, J = 3.8 Hz), 123.6 (q, J = 3.8 Hz), 122.5, 120.6, 115.0,
60.4, 37.6, 14.4.
IR (Diamond ATR, neat): ν~ = 3373 (w), 1689 (s), 1658 (w), 1626 (m), 1605 (m), 1580 (w),
1510 (w), 1447 (w), 1367 (w), 1329 (s), 1306 (s), 1271 (vs), 1195 (m), 1160 (s), 1119 (vs), 1107
(vs), 1095 (s), 1073 (s), 1023 (m), 918 (w), 834 (w), 800 (w), 769 (m), 756 (m), 701 (m).
MS (EI, 70 eV): m/z (%) = 323 (M+, 81), 295 (22), 278 (100), 250 (24), 233 (11), 180 (19), 150
(5).
HRMS (C17H16O2NF3): calculated: 323.1133 found: 323.1120.
3-(4-Fluorophenyl)quinoline (19g)
According to TP18 (4-fluorophenyl)zinc pivalate (18d; 962 mg, 950 mg/mmol, 1.01 mmol) was
dissolved in dry THF (4.0 mL). 3-bromoquinoline (175 mg, 0.84 mmol) and PEPPSI-iPr (14 mg,
0.02 mmol) were added and the mixture was stirred for 1 h at 25 °C. Purification by flash
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS SOLID ZINC REAGENTS
162
chromatography (pentane/diethyl ether = 4:1) afforded the biphenyl 19g (185 mg, 99%) as white
solid.
Mp. : 107.7-109.6 °C. 1H-NMR (300 MHz, CDCl3): δ = 9.15 (s, 1H), 8.26 (s, 1H), 8.16 (d, J = 8.6 Hz, 1H), 7.88 (d, J
= 8.0 Hz, 1H), 7.76-7.56 (m, 4H), 7.28-7.19 (m, 2H). 13C-NMR (75 MHz, CDCl3): δ = 164.5 (d, J = 247 Hz), 149.6, 147.2, 134.0 (d, J = 3.8 Hz),
133.1, 133.0, 132.9, 129.5. 129.2, 129.1 (d, J = 7.1 Hz), 127.9, 127.2, 116.2 (d, J = 21.5 Hz).
IR (Diamond ATR, neat): ν~ = 1603 (m), 1517 (m), 1494 (m), 1468 (m), 1463 (m), 1434 (m),
1337 (m), 1235 (m), 1224 (m), 1198 (m), 1166 (m), 1145 (m), 1124 (m), 1107 (m), 953 (m), 830
(vs), 808 (m), 784 (m), 772 (m), 746 (s), 659 (m).
MS (EI, 70 eV): m/z (%) = 223 (M+, 100), 194 (8), 175 (6), 169 (4), 98 (5).
HRMS (C15H10NF): calculated: 223.0797 found: 223.0783.
Ethyl 4-(1-(phenylsulfonyl)-1H-indol-3-yl)benzoate (19h)
According to TP18 (4-(ethoxycarbonyl)phenyl)zinc pivalate (18e; 1.51 g, 1100 mg/mmol,
1.37 mmol) was dissolved in dry THF (5.0 mL). 3-bromo-1-(phenylsulfonyl)-1H-indole (387 mg,
1.15 mmol) and PEPPSI-iPr (19 mg, 0.03 mmol) were added and the mixture was stirred for 1 h
at 25 °C. Purification by flash chromatography (pentane/diethyl ether = 4:1) afforded the title
compound 19h (311 mg, 91%) as white solid.
Mp. : 116.2-118.4 °C. 1H-NMR (300 MHz, CDCl3): δ = 8.16-8.10 (m, 2H), 8.09-8.05 (m, 1H), 7.96-7.92 (m, 2H),
7.80-7.76 (m, 2H), 7.70-7.65 (m, 2H), 7.58-7.51 (m. 1H), 7.48-7.42 (m, 2H), 7.40-7.35 (m, 1H),
7.34-7.28 (m, 1H), 4.41 (t, J = 7.2 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H). 13C-NMR (75 MHz, CDCl3): δ = 166.3, 138.0, 137.6, 135.5, 134.0, 130.1, 129.4, 129.3, 128.8,
127.6, 126.8, 125.2, 123.9, 123.6, 123.1, 120.3, 113.9, 61.0, 14.3.
IR (Diamond ATR, neat): ν~ = 3141 (vw), 2989 (vw), 2979 (w), 1701 (s), 1609 (m), 1581 (w),
1442 (m), 1366 (s), 1355 (m), 1346 (w), 1338 (w), 1309 (w), 1282 (s), 1272 (s), 1243 (m), 1175 (vs),
1153 (m), 1138 (vs), 1122 (m), 1106 (s), 1088 (m), 1075 (m), 1024 (m), 1010 (s), 997 (m), 974 (w),
931 (m), 854 (m), 838 (w), 826 (w), 774 (s), 767 (m), 763 (m), 745 (s), 738 (vs), 721 (s), 696 (m),
689 (s), 669 (m)
MS (EI, 70 eV): m/z (%) = 405 (M+, 40), 264 (100), 236 (23), 191 (9), 164 (7).
HRMS (C23H19O4NS): calculated: 405.1035 found: 405.1024.
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS SOLID ZINC REAGENTS
163
2,4-Dimethoxy-5-(pyrazin-2-yl)pyrimidine (19i)
According to TP18 (2,4-dimethoxypyrimidin-5-yl)zinc pivalate (18i; 1.27 g, 1362 mg/mmol,
0.93 mmol) was dissolved in dry THF (5.0 mL). 2-chloropyrazine (90 mg, 0.78 mmol) and
PEPPSI-iPr (13 mg, 0.02 mmol) were added and the mixture was stirred for 12 h at 50 °C.
Purification by flash chromatography (pentane/diethyl ether = 1:1) afforded the product 19i
(160 mg, 94%) as white solid.
Mp. : 116.8-118.8 °C. 1H-NMR (300 MHz, CDCl3): δ = 9.12 (d, J = 1.5 Hz, 1H), 8.93 (s, 1H), 8.59-8.56 (m, 1H), 8.45
(d, J = 2.6 Hz, 1H), 4.09 (s, 3H), 4.03 (s, 3H). 13C-NMR (75 MHz, CDCl3): δ = 168.1, 165.5, 160.2, 147.8, 144.9, 144.0, 142.7. 111.6, 55.1,
54.3.
IR (Diamond ATR, neat): ν~ = 3106 (w), 3021 (w), 3016 (w), 1592 (w), 1551 (w), 1546 (w),
1473 (w), 1457 (w), 1391 (vs), 1378 (s), 1325 (m), 1298 (w), 1287 (m), 1246 (m), 1241 (m), 1181
(m), 1140 (w), 1085 (m), 1061 (m), 1010 (m), 995 (s), 988 (s), 929 (m), 844 (m), 793 (m), 776 (w),
763 (w), 756 (m), 661 (m)
MS (EI, 70 eV): m/z (%) = 218 (M+, 100), 203 (23), 188 (37), 146 (13), 118 (13).
HRMS (C14H10O2N4): calculated: 218.0804 found: 218.0798.
(4-(3-Methoxybenzyl)phenyl)(phenyl)methanone (19j)
a) Cross-Coupling in THF
According to TP18 (3-methoxybenzyl)zinc pivalate (18h; 1.13 g, 896 mg/mmol, 1.26 mmol) was
dissolved in dry THF (5.0 mL). 4-Chlorobenzophenone (230 mg, 1.06 mmol) and PEPPSI-iPr
(20 mg, 0.03 mmol) were added and the mixture was stirred for 2 h at 25 °C. Purification by flash
chromatography (pentane/diethyl ether = 5:1) afforded the benzophenone 19j (231 mg, 73%) as
a pale yellow solid.
b) Cross-Coupling in EtOAc
According to TP18 (3-methoxybenzyl)zinc pivalate (18h; 1.81 g, 2105 mg/mmol, 0.86 mmol) was
dissolved in EtOAc (4.0 mL). 4-Chlorobenzophenone (157 mg, 0.72 mmol) and PEPPSI-iPr
(12 mg, 0.03 mmol) were added and the mixture was stirred for 2 h at 25 °C. Purification by flash
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS SOLID ZINC REAGENTS
164
chromatography (silica gel, pentane / Et2O = 5:1) afforded the benzophenone 19j (203 mg, 93%)
as a pale yellow solid.
c) Cross-Coupling in THF using Pd(OAc)2 and S-Phos
According to TP18 (3-methoxybenzyl)zinc pivalate (18h; 1.20 g, 839 mg/mmol, 1.43 mmol) was
dissolved in dry THF (5.0 mL). 4-Chlorobenzophenone (260 mg, 1.20 mmol), Pd(OAc)2 (7.0 mg,
2 mol%) and S-Phos (24 mg, 4 mmol%) were added and the mixture was stirred for 2 h at 25 °C.
Purification by flash chromatography (pentane/diethyl ether = 5:1) afforded the benzophenone
19j (258 mg, 71%) as a pale yellow solid.
Mp. : 117-118 °C. 1H-NMR (300 MHz, CDCl3): δ = 7.83-7.76 (m, 4H), 7.63-7.58 (m, 1H), 7.52-7.47 (m, 2H),
7.35-7.32 (m, 2H), 7.28-7.24 (m, 1H), 6.85-6.79 (m, 3H), 4.06 (s, 2H), 3.81 (s, 3H). 13C-NMR (75 MHz, CDCl3): δ = 196.4, 159.8, 145.9, 141.6, 137.8, 135.5, 132.2, 130.4, 129.9,
129.6, 128.8, 128.2, 121.4, 114.9, 111.5, 55.2, 41.9.
IR (Diamond ATR, neat): ν~ = 3055 (vw), 3026 (vw), 2934 (w), 2834 (w), 1653 (s), 1596 (s),
1582 (m), 1487 (m), 1464 (w), 1446 (m), 1441 (m), 1412 (m), 1316 (m), 1275 (s), 1255 (s), 1176
(m), 1147 (s), 1047 (m), 938 (m), 922 (s), 844 (m), 778 (s), 724 (s), 698 (vs).
MS (EI, 70 eV): m/z (%) = 302 (M+, 100), 225 (63), 165 (12), 105 (26), 77 (15).
HRMS (C21H18O2): calculated: 302.1307 found: 362.1308.
4'-Methoxy-[1,1'-biphenyl]-2-carbaldehyde (19k)
According to TP18 (4-methoxyphenyl)zinc pivalate (18a; 2.33 g, 956 mg/mmol, 2.44 mmol) was
dissolved in dry THF (5.0 mL). 2-bromobenzaldehyde (379 mg, 2.05 mmol) and PEPPSI-iPr
(33 mg, 0.05 mmol) were added and the mixture was stirred for 1 h at 25 °C. Purification by flash
chromatography (pentane/diethyl ether = 10:1) afforded the biphenyl 19k (349 mg, 82%) as
white solid.
Mp. : 56.6-58.4 °C. 1H-NMR (300 MHz, CDCl3): δ = 10.0 (s, 1H), 8.06-8.00 (m, 1H), 7.68-7.60 (m, 1H), 7.52-7.42
(m, 2H), 7.37-7.27 (m, 2H), 7.07-6.98 (m, 2H), 3.89 (s, 3H). 13C-NMR (75 MHz, CDCl3): δ = 192.6, 159.7, 145.6, 133.7, 133.5, 131.2, 130.7, 130.0, 127.6,
127.3, 113.9, 55.3.
IR (Diamond ATR, neat): ν~ = 2938 (w), 2844 (w), 1689 (s), 1658 (m), 1605 (m), 1596 (s),
1576 (m), 1511 (m), 1475 (m), 1464 (m), 1456 (m), 1448 (m), 1442 (m), 1416 (w), 1393 (m), 1309
(w), 1296 (m), 1270 (m), 1243 (vs), 1196 (s), 1179 (s), 1167 (m), 1114 (m), 1099 (m), 1048 (w),
C. EXPERIMENTAL SECTION PRODUCT SYNTHESIS SOLID ZINC REAGENTS
165
1030 (s), 1015 (m), 999 (m), 972 (w), 951 (w), 844 (s), 830 (s), 802 (m), 764 (vs), 744 (m), 724 (m),
709 (m)
MS (EI, 70 eV): m/z (%) = 212 (M+, 100), 197 (15), 185 (10), 181 (20), 169 (29), 152 (10), 141
(30), 115 (17).
HRMS (C14H12O2): calculated: 212.0837 found: 212.0824.
Preparation of Carbonyl Addition Products
(2-Bromophenyl)(4-methoxyphenyl)methanol (49)
According to TP19 (4-methoxyphenyl)zinc pivalate (18a; 1.24 g, 953 mg/mmol, 1.30 mmol) was
dissolved in dry THF (5.0 mL). 2-Bromobenzaldehyde (204 mg, 1.10 mmol) was added and the
mixture was stirred for 2 h at 25 °C. Purification by flash chromatography (pentane/diethyl ether
= 3:1) afforded the alcohol 49 (232 mg, 72%) as colourless oil. 1H-NMR (300 MHz, CDCl3): δ = 6.64-7.61 (m, 1H), 7.53 (m, 1H), 7.37-7.27 (m, 3H), 7.16-7.11
(m, 1H), 6.88-6.83 (m, 2H), 6.12 (s, 1H), 3.78 (s, 3H). 13C-NMR (75 MHz, CDCl3): δ = 159.2, 142.7, 134.4, 132.8, 129.0, 128.4, 128.2, 127.6, 122.7,
113.9, 74.5, 55.2.
IR (Diamond ATR, neat): ν~ = 3338 (w), 2932 (w), 2836 (w), 2362 (vw), 1736 (vw), 1610 (m),
1586 (w), 1510 (s), 1464 (m), 1438 (m), 1304 (m), 1246 (vs), 1172 (s), 1110 (w), 1016 (s), 830 (m),
804 (m), 778 (m), 746 (vs), 682 (m), 624 (w).
MS (EI, 70 eV): m/z (%) = 292 (M+, 47), 261 (11), 195 (13), 183 (26), 152 (22), 137 (66), 109
(100), 94 (13), 77 (32), 51 (11).
HRMS (C14H13BrO2): calculated: 292.0099 found: 292.0078.
D. APPENDIX
CURRICULUM VITAE
THOMAS KUNZ
BORN ON JANUARY 26th, 1982
IN MUNICH, GERMANY
EDUCATION
09/2008-10/2011 LUDWIG-MAXIMILIANS-UNIVERSITY MUNICH, GERMANY
PhD Thesis in organic chemistry in the workgroup of Prof. Dr. P. Knochel.
10/2005 – 08/2007 LUDWIG-MAXIMILIANS-UNIVERSITY MUNICH, GERMANY
Master of Science Chemistry program, Graduation with distinction. Master’s Thesis in inorganic chemistry in the workgroup of Prof. Dr. T. Klapötke.
10/2001 - 08/2005 LUDWIG-MAXIMILIANS-UNIVERSITY MUNICH, GERMANY
Bachelor of Science Chemistry and Biochemistry program, Bachelor Thesis in organic chemistry in the workgroup of Prof. Dr. P. Knochel.
09/1992 - 06/2001 MAX-PLANCK-GYMNASIUM MUNICH, GERMANY
Secondary education, graduation: „Allgemeine Hochschulreife“.
PUBLICATIONS
Thomas Kunz, Paul Knochel: Selective Multiple Magnesiations of the Thieno[3,2-b]thiophene Scaffold. Chemistry - A European Journal 2011, 17(3), 866-872.
Sebastian Bernhardt, Georg Manolikakes, Thomas Kunz, Paul Knochel: Preparation of Solid Salt-Stabilized Functionalized Organozincs – Application to Cross-Couplings and Carbonyl Additions. Angew. Chem. 2011, 123, 9372-9375; Angew. Chem. Int. Ed. 2011, 50, 9205-9208.
since 07/2010 Contributor of Thieme Chemistry SYNFACTS
AWARDS
2006 Römer-Award for excellent scientific achievements
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